Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1/[CH:4]=[N:20]/[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.4 %

Procedure:
A mixture of 2-fluoro-5-(trifluoromethyl)benzaldehyde (1.00 g, 5.21 mmol), (S)-2-methylpropane-2-sulfinamide (631 mg, 5.21 mmol), and copper sulfate (1.66 g, 10.4 mmol) in dichloromethane is stirred at room temperature for 12 hours. Additional copper sulfate (1.66 g, 10.4 mmol) is added, and the mixture is stirred at room temperature for 5 hours. Then, the mixture is filtered through a pad of Celite, and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1) to give 314 mg (20% yield) of the title compound as colorless oil.
Reaction SMILES: BrB(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14].CO>ClCCl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14]
Reactant: COc1ccccc1S(=O)(=O)N(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccccc1O
Temperature: -70 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
200 ml (200 mmol, 4.9 eq) of a 1 M solution of tribromoborane in dichloromethane were added dropwise to a solution of 8.78 g (40.8 mmol, 1 eq) of 2-methoxy-N,N-dimethylbenzenesulfonamide in 250 ml of dichloromethane at −70° C. under nitrogen. The reaction medium was left at −70° C. for one hour and was then left to return to 10° C. for one and a half hours. The reaction medium was then cooled to −70° C. and approximately 100 ml of methanol were added dropwise (approximately one hour of addition). The reaction medium was then left to return to ambient temperature and was concentrated. The residue obtained was filtered off on silica with the eluent 6/4 heptane/ethyl acetate. 7.81 g of product were obtained in the form of a beige solid. Yield=95%.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[ClH:6].Cl.Cl.[CH:9]([C@H:22]1[N:27]2[CH2:28][CH2:29][NH:30][CH2:31][C@H:26]2[CH2:25][N:24]([CH2:32][C:33]2[CH:38]=[C:37]([N:39]3[C:43]([C:44]([F:47])([F:46])[F:45])=[N:42][N:41]=[N:40]3)[CH:36]=[CH:35][C:34]=2[O:48][CH3:49])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>ClCCl>[ClH:5].[ClH:6].[CH:9]([C@H:22]1[N:27]2[CH2:28][CH2:29][N:30]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:31][C@H:26]2[CH2:25][N:24]([CH2:32][C:33]2[CH:38]=[C:37]([N:39]3[C:43]([C:44]([F:47])([F:46])[F:45])=[N:42][N:41]=[N:40]3)[CH:36]=[CH:35][C:34]=2[O:48][CH3:49])[CH2:23]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@@H]2CNCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@@H]2CN(S(C)(=O)=O)CCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
Methanesulfonyl chloride (22.1 mg) was added to a mixture of (4R,9aS)-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine trihydrochloride (100 mg) and N,N-diisopropylethylamine (116 μl) in dichloromethane under ice-cooling. After being stirred at the same temperature for 2 hours the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulphate, and evaporated under reduced pressure. The resulting oil was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol. The fractions containing the objective compound was collected and evaporated under reduced pressure and the resulting residue was treated with 4N hydrogen chloride in ethyl acetate to give (4R,9aR)-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-8-(methylsulfonyl)octahydro-2H-pyrazino[1,2-a]pyrazine dihydrochloride (52.8 mg) as colourless powder.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](F)(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:10]=1>>[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([S:24](=[O:26])(=[O:25])[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[CH:22][CH:23]=2)[N:10]=1
Reactant: CN(C)CCCN
Reactant: N#Cc1cnc(Nc2ccc(S(=O)(=O)F)cc2)nc1N
Product: CN(C)CCCNS(=O)(=O)c1ccc(Nc2ncc(C#N)c(N)n2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
3-Dimethylaminopropylamine (3 ml) was added to 4-amino-5-cyano-2-(4-fluorosulphonylanilino)pyrimidine (Method 1; 250 mg, 0.853 mmol), the mixture was heated at 90° C. for 45 minutes then stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane/methanol (50:50:0) increasing in polarity to (80:0:20). The product was triturated with ether and a few drops of methanol and the resulting solid collected by filtration to give the title compound (176 mg, 55%). NMR: 1.45 (t, 2H), 2.04 (s, 6H), 2.10 (t, 2H), 2.72 (t, 2H), 7.60 (s, 2H), 7.62 (d, 2H), 7.98 (d, 2H), 8.40 (s, 1H); m/z 376 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2[C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=O)[CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+].O>CO>[NH2:24][CH:4]1[CH2:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]2[C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: COC(=O)c1cccc2c1CC(C)(C)CC2=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc2c1CC(C)(C)CC2N
Temperature: 60 °C
Yield: 95.6 %

Procedure:
A solution of 3.0 g (13 mmol) of methyl 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (J. Org. Chem. 17 (1976), 2918) in 45 ml of methanol was treated with 10 g (130 mmol) of ammonium acetate and 5.7 g (90 mmol) of sodium cyanoborohydride and heated at 60° C. for 20 hrs. After addition of 10 ml of water, the mixture was completely concentrated in vacuo and the residue was taken up in EA and aqueous ammonia. The organic phase was washed with water, dried over magnesium sulfate and concentrated in a rotary evaporator, and 2.9 g of methyl 5-amino-7,7-dimethyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylate were obtained.
Reaction SMILES: [NH:1]1[CH:6]([CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:9][OH:10].I[CH2:12][C:13]#[N:14].CCN(CC)CC>CN(C=O)C>[OH:10][CH2:9][CH:2]1[CH2:3][CH2:4][CH2:5][CH:6]([CH2:7][OH:8])[N:1]1[CH2:12][C:13]#[N:14]
Reactant: OCC1CCCC(CO)N1
Reactant: N#CCI
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCN1C(CO)CCCC1CO
Yield: 51.8 %

Procedure:
The method follows that of S5. 2,6-piperidinedimethanol (3.80 g, 26.21 mmol), iodoacetonitrile (5.24 g, 31.45 mmol), Et3N (4.38 mL, 31.45 mmol) and dry DMF (20 mL). Purification by flash chromatography using CH2Cl2/CH3OH (9:1) as eluent afforded the title compound as a straw-coloured oil (2.5 g, 53%). FAB MS, m/z(M+H)+ 185.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24]3)[CH:8]=2)[N:3]=1.[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31]>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3([C:27]([NH:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:25][CH2:26]3)[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)N
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C3(C(=O)O)CCC3)ccc2n1
Product: CC(C)(C)NC(=O)C1(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CCC1

Procedure:
(Preparation by reaction of 1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutanecarboxylic acid [“A61”] with tert-butylamine)
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].Cl.[C:12]([NH:16][NH2:17])([CH3:15])([CH3:14])[CH3:13].Cl.N>O.CO>[NH2:6][C:5]1[N:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:17]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: CC(C)(C)NN
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: CC(C)(C)n1ncc(N=O)c1N
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 2.70 g (21 mmol) of t-butylhydrazine hydrochloride with a purity of 97% by weight, 1.4 ml of water, 6 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 60 to 62° C. for 3 hours. After completion of the reaction, 5 ml of water was added to the mixture and the mixture was cooled up to 10° C. Then, 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 1.2 ml of cold water and 1.2 ml of cold methanol, and dried under reduced pressure to obtain 1.93 g of 5-amino-1-t-butyl-4-nitrosopyrazole (Isolation yield: 55.2%) as reddish orange solid with a purity of 96.2% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C.[C:25]([O:29][C:30](=[O:48])[NH:31][CH2:32][CH2:33][NH:34][C:35](=[O:47])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[CH:38][CH:37]=1)([CH3:28])([CH3:27])[CH3:26]>CO>[C:25]([O:29][C:30](=[O:48])[NH:31][CH2:32][CH2:33][NH:34][C:35](=[O:47])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:14]([NH2:17])=[N:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[CH:38][CH:37]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CCCCN)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Reaction time: 2 h
Yield: 86.8 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.32 g, 0.82 mmol) and triethylamine (0.27 mL, 1.64 mmol) were sequentially added into a solution of 33 (0.39 g, 0.82 mmol) in 5 mL of methanol. The reaction mixture was stirred in the boiling solvent for 2 h. The solvent was evaporated and the residue was separated by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 34 (0.39 g, 62%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.07 (t, 2H), 1.38 (s, 9H), 1.52 (m, 2H), 1.65 (m, 2H), 2.66 (m, 2H), 3.10 (m, 2H), 3.28 (m, 2H), 4.39 (m, 1H), 6.65 (br s, 1H), 6.94 (m, 1H), 7.28 (m, 2H), 7.75 (d, 2H), 8.49 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][C:14](=N)[C:13]=2[C:27]#[N:28])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C([O-])(O)=[O:30].[Na+]>C1COCC1.O.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][C:14](=[O:30])[C:13]=2[C:27]#[N:28])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: O=C([O-])O
Reactant: COc1cc(-c2c(C#N)c(=N)oc3c2ccc2c3ccn2C)cc(Br)c1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2c(C#N)c(=O)oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 18 %

Procedure:
To a solution of 4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-7-methyl-2H-pyrrolo[2,3-h]chromene (100 mg, 0.216 mmol) in THF:water (10:2) was added a ZnCl2 solution (1 mL, 1.0 M in CH2Cl2). The solution was stirred at room temperature for approximately 7 h. The reaction mixture was made basic with saturated NaHCO3 (10 mL), and extracted with EtOAc (2×25 mL). The EtOAc extracts were washed with brine (10 mL), dried over MgSO4, and evaporated to yield a yellow solid. The solid was purified by flash column chromatography (silica gel, EtOAc:hexanes 30-70% EtOAc) to yield 17 mg (18%) of the product as a yellow solid. 1H NMR (acetone-d6): 7.51-7.48 (m, 2H), 7.42 (d, J=1.8 Hz, 1H), 7.34 (d, J=2.1 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 6.91 (dd, J=0.6, 3.3 Hz, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([N:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH3:21])[N:16]=[CH:17]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([N:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=3)[CH3:21])[N:16]=[CH:17]2)=[CH:12][CH:11]=1
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2cn1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3cn2)cc1
Yield: 80.4 %

Procedure:
A mixture of ethyl 2-bromopropionate (0.64 g), 4-[N-(7-chloroisoquinolin-3-yl)-N-methylamino]phenol (0.92 g), anhydrous potassium carbonate (0.49 g) and methyl ethyl ketone was heated under reflux for a period of 5 hours. The solution was cooled, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the product was purified by column chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(7-chloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.00 g) as a green oil. The assigned structure was confirmed by proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.25 (3H, t); 1.60 (3H, d); 3.45 (3H, s); 4.22 (2H, q); 4.75 (1H, q); 6.52 (1H, s); 6.8-7.4 (6H, m); 7.62 (1H, m); 8.75 (1H, s).
Reaction SMILES: CC1(C)[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:27])[C@H:5]2[C:10]([CH3:26])([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])[CH3:11].CC(C)=[O:31].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:26][C:10]([C@@H:5]1[C:4](=[O:27])[NH:3][C@@H:6]1[CH2:7][C:8]([OH:31])=[O:9])([O:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)=[O:14])[CH3:11]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H]1CCOC2(C)C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)O
Reaction time: 0.5 h

Procedure:
A solution of (6R,7R)-2,2-dimethyl-7-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-aza-3-oxabicyclo[4.2.0]octan-8-one (11.99 g) in acetone (119.9 ml) was added dropwise to a solution of 2N Jones reagent (38.13 ml) in acetone (119.9 ml) at ambient temperature over a period of an hour, and the mixture was stirred for an additional 30 minutes. After addition of an excess of isopropyl alcohol to the mixture, the solvent was removed by evaporation. The residue was dissolved in ethyl acetate (1 l) and the solution was washed with water. The aqueous washings were extracted with ethyl acetate (200 ml). The organic layers were combined, washed with an aqueous sodium chloride, dried over magnesium sulfate, and evaporated to give 2-[(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxo-azetidin-2-yl]acetic acid (11.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.N1C=CC=CC=1>O>[C:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Oc1ccc(Cl)cc1C(=O)c1ccccc1)c1cccnc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
15 g (64.5 mmol) of p-chlorobenzoylphenol and 12 g (68 mmol) of nicotinic acid chloride hydrochloride was mixed with 200 ml dry pyridine and stirred for 24 hours at 40° C. After cooling 200 ml water were added and the precipitated product washed twice with 80 ml of water and recrystallized from methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].Br[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1>C1COCC1.C(OCC)C.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[S:13]1[CH:14]=[CH:15][C:11]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:12]1
Reactant: Brc1ccsc1
Reactant: Cc1ccc(Br)cc1
Agent: Cl[Ni]Cl
Agent: [Mg]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(-c2ccsc2)cc1
Reaction time: 0.17 h

Procedure:
A solution of 4-bromotoluene (0.9 ml, 7.3 mmol) in THF (3 ml) is added to dried magnesium turnings (0.815 g, 33.5 atoms) under nitrogen atmosphere. After the exothermic reaction initiates, a solution of 4-bromotoluene (3.16 ml, 25.7 mmol) in THF (3 ml) is dropped to the reaction mixture. The stirring is continued for 10 min. The mixture is dropped to a suspension of 3-bromothiophene (2.8 ml, 29.9 mmol) and [1,2-bis(diphenylphosphino)-ethane]nickel(II) chloride (0.72 g, 1.4 mmol) in diethyl ether (50 ml), which has been stirred for 10 min. The reaction mixture is cooled and quenched with 1N hydrochloric acid and extracted with ether. The organic layer is washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate and concentrated in vacuo. The residue is recrystallized from ethanol to give 4-(3-thienyl)toluene.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[F:25][C:26]1([F:38])[O:30][C:29]2[CH:31]=[CH:32][C:33](B(O)O)=[CH:34][C:28]=2[O:27]1.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[F:38][C:26]1([F:25])[O:27][C:28]2[CH:34]=[CH:33][C:32]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)=[CH:31][C:29]=2[O:30]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OB(O)c1ccc2c(c1)OC(F)(F)O2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OC(F)(F)O4)n2n1
Temperature: 110 °C
Yield: 38.7 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 2,2-difluorobenzo[d][1,3]dioxol-5-ylboronic acid (46 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (60-75% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (31.4 mg, 39%). 1H NMR (DMSO-d6) δ: 11.21 (s, 1H), 8.62 (d, J=1.3 Hz, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.05 (s, 1H), 7.99-8.04 (m, 3H), 7.93 (d, J=5.3 Hz, 1H), 7.67 (d, J=5.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 6.41 (s, 1H), 5.20 (s, 1H), 2.41 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 467.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([CH:25]=O)=[C:20]([F:27])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[N:8]1)=[O:4].[NH2:30][CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1C=CC=CC=1>[CH3:29][C:2]([CH3:1])([CH3:28])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([CH2:25][NH:30][CH:31]4[CH2:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH2:32]4)=[C:20]([F:27])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[N:8]1)=[O:4]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(C)(C)C(=O)OCn1cnc(-c2cccc(-c3cc(F)c(C=O)c(F)c3)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)OCn1cnc(-c2cccc(-c3cc(F)c(CNC4Cc5ccccc5C4)c(F)c3)c2)n1
Reaction time: 1.5 h

Procedure:
A mixture of [3-(3′,5′-difluoro-4′-formyl-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate (67.6 g; 0.17 mol; I-X-9), 2-aminoindane (22.9 g; 0.17 mol; freebase obtained commercially) and HOAc (0.48 mL; 0.0085 mol, Note 1) in PhH (350 mL) was heated under reflux using a Dean-Stark trap to remove water. After 1.5 h, volatiles were removed in vacuo, the residue was dissolved in CH2Cl2/HOAc (400:25 mL respectively), and NaBH(OAc)3 (43 g; 0.203 mol) was added at room temperature. The mixture was stirred 12 h, and quenched by dropwise addition of water (250 mL). The mixture was stirred 30 min and separated into layers. The organic layer was washed (satd NaHCO3, brine), filtered through a pad of Na2SO4 and concentrated in vacuo. The residue was triturated with MeOH (250 mL), the resulting slurry was diluted with water (250 mL) and stirred 30 min at room temperature. Solids were collected by filtration, and washed with water. The cake was air-dried overnight on the filter, affording the title compound as an off-white solid, used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.1 (s, 9 H), 2.74 (dd, J=15.7, 6.1 Hz, 2 H), 3.09 (dd, J=15.8, 7.1 Hz, 2 H), 3.54 (quint, J=6.6 Hz, 1 H), 3.86 (s, 2 H), 6.21 (s, 2 H), 7.07-7.13 (m, 2 H), 7.15-7.21 (m, 2 H), 7.43-7.52 (m, 2 H), 7.60 (t, J=7.7 Hz, 1 H), 7.81 (ddd, J=7.9, 1.8, 1.1 Hz, 1 H), 8.06 (ddd, J=7.8, 1.3, 1.2 Hz, 1 H), 8.26 (t, J=1.7 Hz, 1 H), 8.82 (s, 1 H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([CH3:18])=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=C(C)c1ccc(NC(C)=O)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)c1ccc(NC(C)=O)nc1
Reaction time: 48 h

Procedure:
A solution of (E/Z) ethyl 3-(6-acetylamino-pyrid-3yl)-but-2-enoate (27.3 g, Reference Example 22) in ethanol (500 mL) was hydrogenated (3bar hydrogen pressure) at 50° C. using 10% palladium on charcoal (1.0 g) as catalyst. After 48 h, the mixture was degassed, filtered through a pad of diatomaceous earth and the pad rinsed through with ethanol. The filtrate was evaporated to give the title compound as an oil.