Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:17]Br>C1COCC1.[Cl-].[Na+].O>[Br:17][C:11]1[C:10]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:9]=2[S:8][C:7]=1[N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: BrBr
Reactant: O=C1CCCc2cc(N3CCOCC3)sc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCc2c1sc(N1CCOCC1)c2Br
Yield: 71.4 %

Procedure:
To a stirred solution of Example 2 (0.83 g, 3.50 mmol) in THF (50 mL) at 0° C. was added, dropwise, Br2 (0.56 g, 3.50 mmol) and the reaction mixture was stirred for 20 minutes. The reaction mixture was then poured into brine (200 mL) and extracted with EtOAc (3×100 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 1:5 EtOAc/hexanes) gave the title compound as a pale brown solid (0.79 g, 72%). δH (DMSO-d6) 3.77-3.74 (4H, m), 3.22-3.18 (4H, m), 2.70-2.67 (2H, m), 2.52-2.47 (2H, m), 2.10-2.04 (2H, m). δ 13C (DMSO-d6) 189.7, 160.2, 152.7, 124.6, 97.4, 65.9 (2×CH2), 51.9 (2×CH2), 37.3, 25.9, 23.4. LCMS (ES+) 315.0 and 317.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11][CH2:10]2)[C:5]([F:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[C:21]([F:36])=[CH:22][C:23]([CH:33]2[CH2:35][CH2:34]2)=[C:24]([N:26]2[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]2)[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[F:18][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:19][C:20]2[C:21]([F:36])=[CH:22][C:23]([CH:33]3[CH2:35][CH2:34]3)=[C:24]([N:26]3[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]3)[CH:25]=2)=[N:3][CH:4]=1
Reactant: Cn1nnn(-c2cc(N)c(F)cc2C2CC2)c1=O
Reactant: Fc1cnc(Cl)nc1NC1CCN2CCCC2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(NC4CCN5CCCC5C4)n3)c(F)cc2C2CC2)c1=O
Temperature: 70 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
A mixture of N-(2-chloro-5-fluoropyrimidin-4-yl)octahydroindolizin-7-amine (54 mg, 0.2 mmol), 1-(5-amino-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5-one (52 mg, 0.21 mmol; prepared according to US20110130415 pages 43-48, which is hereby incorporated by reference in its entirety) and para-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) in isopropyl alcohol (3 ml) were combined in a sealed vial, heated to 70° C. and stirred for 2 days. After cooling, the mixture was concentrated under vacuum to leave a crude residue. The residue was purified by preparative high-performance liquid chromatography to give a solid. The solid was partitioned between EtOAc (20 ml) and 1N NaOH (20 ml). The aqueous layer was extracted with EtOAc (2×20 ml) and the combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave the product (46 mg, 47%) as a solid after freeze-drying from MeCN/H2O.
Reaction SMILES: CS(C)=O.[CH:5]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17](F)[CH:18]=3)[C:13](=[O:22])[C:12]([N+:23]([O-:25])=[O:24])=[CH:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O>[CH:26]1([NH:32][C:17]2[CH:18]=[C:19]3[C:14]([C:13](=[O:22])[C:12]([N+:23]([O-:25])=[O:24])=[CH:11][N:10]3[CH:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:15][C:16]=2[F:21])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCCCC1
Reactant: O=c1c([N+](=O)[O-])cn(C2CCCC2)c2cc(F)c(F)cc12
Solvent: CS(C)=O
Solvent: O
Product: O=c1c([N+](=O)[O-])cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a 40 ml DMSO solution of 2.0 g of 1-cyclopentyl-6,7-difluoro-3-nitroquinolin-4(1H)-one was added 2.3 ml of cyclohexylamine, followed by overnight stirring at 90° C. The reaction mixture was cooled to room temperature and poured into ice-cooled water, and then the insoluble materials were collected by filtration. By recrystallizing the resulting solid from ethanol, 2.5 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-nitroquinolin-4(1H)-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[C:10]([CH:14]=[S:15](=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:18]([CH3:21])([O-:20])=[O:19].C(O)(=O)C.C([O-])(=O)C.[NH4+]>O>[Cl:1][C:2]1[C:11]([CH:12]=[CH:21][N+:18]([O-:20])=[O:19])=[C:10]([CH:14]=[S:15](=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C=S(=O)=O)c(C=O)c1Cl
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C=S(=O)=O)c(C=C[N+](=O)[O-])c1Cl

Procedure:
With the exclusion of atmospheric moisture, 50 g (0.18 mol) of methyl 2-chloro-3-formyl-4-sulfonylmethylbenzoate, 220 g (3.6 mol) of nitromethane, 216 g (3.6 mol) acetic acid and 7 g (91 mmol) of ammonium acetate are stirred at 85° C. The reaction mixture is poured into 2 l of distilled water and extracted with diethyl ether. The organic phase is washed with saturated aqueous sodium bicarbonate solution, dried with sodium sulfate, filtered and freed from the solvent under reduced pressure. The crude product is recrystallized from n-hexane/ethyl acetate. Yield: 13.1 g, m.p. 147-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][C:6]2([CH3:16])[CH3:15].[C:17]([CH2:23][C:24]#[N:25])(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C(O)(=O)CC.C([O-])(=O)C.[NH4+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[C:23]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:24]#[N:25])[CH2:7][C:6]2([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1cc2c(cc1OC)C(C)(C)CC2=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCC(=O)O
Solvent: Cc1ccccc1C
Product: COc1cc2c(cc1OC)C(C)(C)CC2=C(C#N)C(=O)C(C)(C)C
Temperature: 120 °C
Yield: 50 %

Procedure:
44 g (0.2 mol) of 5,6-dimethoxy-3,3-dimethyl-1-indanone, 25 g (0.2 mol) of pivaloylacetonitrile, 32 g of propionic acid and 17 g of ammonium acetate are mixed in 80 g of xylene and heated at 120° C. for 7 hours. After the system has been cooled to room temperature and the organic phase has been washed, the xylene is distilled off, and the crude product which remains is recrystallized in methanol. Yield: 50% theory; E1/1730 (λmax 373 nm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C(=O)N([I:17])C(=O)C1>CC(O)=O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([I:17])=[C:4]([NH2:9])[CH:3]=1
Reactant: Nc1ccc(Cl)c(Br)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Nc1cc(Br)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.5 %

Procedure:
To a solution of 3-bromo-4-chlorobenzenamine (10.0 g, 48.5 mmol) in CH3COOH (50 mL), NIS (10.9 g, 48.5 mmol) was added in portions and the resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=50:1) to afford the desired product (2.5 g, 15.5% yield). ESI-MS m/z: 329.9 [M−H]−.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C@@H:5]([NH:9][C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C:6]([OH:8])=O.N=C=N.Cl.[CH3:31][O:32][C:33](=[O:36])[CH2:34][NH2:35].C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:16]1[C:15]2[CH:14]([CH2:13][O:12][C:10]([NH:9][C@@H:5]([C:6]([NH:35][CH2:34][C:33]([O:32][CH3:31])=[O:36])=[O:8])[CH2:4][CH2:3][CH2:2][CH3:1])=[O:11])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: COC(=O)CN
Agent: Cl
Agent: N=C=N
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of fmoc-D-Nle-OH (10 g, 28.3 mmol, Novabiochem) and PS-carbodiimide (33 g, 42.45 mmol, 1.28 mmol/g, Argonaut Technologies Inc.) in dichloromethane (250 mL) was stirred at room temperature for 0.5 h. Then, glycine methyl ester hydrochloride (5.3 g, 42.45 mmol, Aldrich), HOAt (3.8 g, 28.3 mmol, Perseptive Biosystems) and diisopropylethylamine (16 mL, 84.9 mmol, Aldrich) were added and the mixture was stirred at room temperature for 16 h. The mixture was filtered and the resin was washed with dichloromethane (2×70 mL). The filtrate was concentrated in vacuo and the residue was purified by column chromatography, eluting with EtOAc/hexane (1:2) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 425 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[NH:17][C:16](=[O:18])[O:15][N:14]=2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C1(S)C=CC=CC=1>C(O)(C(F)(F)F)=O>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[NH:17][C:16](=[O:18])[O:15][N:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2noc(=O)[nH]2)C1
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c([C@@H]2CCNC2)no1
Reaction time: 24 h
Yield: 91.1 %

Procedure:
Crude (R)-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (872 mg, 3.41 mmol), CH2Cl2 (5 mL) and thiophenol (0.7 mL, 6.8 mmol) were combined and diluted with TFA (5 mL). After 24 h, the reaction was concentrated in vacuo. The residue was partitioned between CH2Cl2 and water. The layers were separated and the CH2Cl2 layer was extracted with water. The combined aqueous layers were concentrated in vacuo. Reverse phase HPLC purification yielded 482 mg of (R)-3-pyrrolidin-3-yl-4H-1,2,4-oxadiazol-5-one as a tan oil (˜50% pure) that was used without further purification.
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:27])=[C:23]([F:26])[CH:24]=3)[NH:19][C:18]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:27][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:28])[C:10]3([CH:9]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[F:36])[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:25]2=[CH:24][C:23]=1[F:26]
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1.8 g, 3.4 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (7 mL). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (2 g, 93%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[NH:14][N:13]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2n[nH]c3c2CCNCC3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 mmol) in CH2Cl2 (5 mL) was added TFA (1 mL). The mixture was stirred at RT for 16 h. After concentration, the intermediate 3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene was obtained. The intermediate (0.1 mmol) was converted to the title compound (16 mg) according to the procedure described in Example 165 using 3,4-dimethoxy-benzaldehyde (0.2 mmol) in place of formaldehyde. MS (ESI): exact mass calculated for C22H24ClN3O2, 397.16; found, m/z 398.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38-7.35 (br m, 4H), 7.91 (d, J=1.8 Hz, 1H), 6.82-6.80 (dd, J=8.1, 1.8 Hz, 1H), 6.76-6.74 (d, J=8.1 Hz, 1H), 3.83-3.80 (s, 6H), 2.84-2.82 (m, 4H), 2.71-2.69 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]([S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH2:14]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH2:19][CH2:18][S:15](=[O:17])(=[O:16])[CH2:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CS(=O)(=O)C=C
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N2CCS(=O)(=O)CC2)C1
Temperature: 25 °C
Yield: 64 %

Procedure:
To a refluxing solution of 3-aminoazetidine-1-carboxylic acid tert-butyl ester (10.0 g, 58.1 mmol) in EtOH (50 mL) was added drop wise a solution of divinyl sulfone (5.9 mL, 6.86 g, 58.1 mmol) in EtOH (50 mL). The resulting mixture was stirred at reflux for 15.5 h, cooled to room temperature and concentrated in vacuo. The resulting beige solid was triturated with Et2O, affording the title compound as a white solid (10.8 g, 64%). 1H NMR (CDCl3, 300 MHz): δ 3.97 (dd, J=8.8, 7.1 Hz, 2 H); 3.76 (dd, J=8.8, 7.1 Hz, 2 H); 3.36-3.26 (m, 1 H); 3.13-3.05 (m, 4 H); 2.90-2.83 (m, 4 H); 1.44 (s, 9 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 150 °C
Yield: 10 %

Procedure:
A mixture of [4-(4-bromo-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (44 mg, 0.10 mmol), 4-methoxy-phenylboronic acid (3 mg, 0.15 mmol), sodium carbonate (21 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) in N,N-dimethylformamide (0.5 mL) was heated in a microwave oven at 150° C. for 30 minutes under an argon atmosphere. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford [4-(4′-methoxy-biphenyl-4-sulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (4.7 mg, 10%) as a white solid. MS cald. for C24H27N3O5S 469, obsd. (ESI+) [(M+H)+] 470.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH2:19][CH2:20][CH2:21][CH2:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=[C:4]([NH2:23])[N:3]=1.[F:24][C:25]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:23][C:4]1[N:3]=[C:2]([C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:24])[CH:32]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH2:19][CH2:20][CH2:21][CH2:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc4c([nH]3)CCCC4)C2)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc5c([nH]4)CCCC5)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A mixture of 4-chloro-6-[2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-4-morpholinyl]-2-pyrimidinamine (208 mg, 0.623 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (200 mg, 0.809 mmol), Na2CO3 (165 mg, 1.557 mmol) and Pd(PPh3)4 (72 mg, 0.062 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was heated at 140° C. under microwave condition with stirring for 1 hour. The mixture was filtered, washed by EtOAc (150 mL), evaporated, and chromatographed (PE-EtOAc, 3:1) to afford the title compound (150 mg) as a yellow solid. LC-MS (ES) m/z=420 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=1>>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]1[N:17]=[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]2[CH:2]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(C#N)ccc2n1
Yield: 11 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-5-cyanopyridine instead of 2-aminopyridine, to the title compound (17 mg, 11%) which was obtained as a light yellow foam. MS: m/e=301.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[S:14][C:15]4[C:16]([N:21]=3)=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][C:6]=2[O:5][CH:4]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[S:14][C:15]4[C:16]([N:21]=3)=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][C:6]=2[O:5][CH:4]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
To a solution of 2-(3-chloromethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine (2.7 g, 8.5 mmol) in DMF (42 mL) at 0° C. was added sodium azide (0.61 g, 9.3 mmol). The mixture was stirred at (rt, 3 h), partitioned between ethyl acetate and brine, dried, filtered and concentrated. Upon addition of ethyl acetate and hexanes, precipitate was formed and filtered. Concentration and purification by silica gel flash chromatography using ethyl acetate/hexanes provided a solid that was combined with the previously filtered precipitate to provide the title compound (1.8 g, 65%). MS (ESI): mass calcd. for C15H9N5O2S, 323.05; m/z found, 324.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (dd, J=4.8, 1.6, 1H), 8.09-7.95 (m, 1H), 7.74-7.64 (m, 3H), 7.36 (dd, J=8.5, 2.1, 1H), 7.22 (dd, J=7.9, 4.8, 1H), 4.50 (s, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)[CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][C:28](=[O:31])[C:29]#[CH:30])[CH3:26]>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH:30]([CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:31])[O:17][C:12]=2[CH:11]=1)=[O:18])[CH2:5][CH2:6][CH3:7]
Reactant: C#CC(=O)OCC
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(CCC)NC(=O)c1ccc2c(c1)OC(CC(=O)OCC)O2
Yield: 71 %

Procedure:
N-(heptan-4-yl)-3,4-dihydroxybenzamide (example 18a) (0.29 mmol, 75 mg) was dissolved in dry acetone with 6 eq excess (242 mg) of potassium carbonate then 1.2 eq excess (36 μl) of propynoic acid ethyl ester was added and a mixture was refluxed for 24 h. The solvent was evaporated and a solid was dissolved in dichloromethane and extracted with 10% NaHCO3 and water. The crude product was purified by chromatography on silica gel to give 72 mg of desired product (71%). 1H NMR (500 MHz, CDCl3): δ 0.91-0.94 (t, 6H), L23-1.30 (m, 4H), 1.37-1.41 (4H), 2.97-2.98 (d, 2H), 3.70-3.74 (dd, 2H), 4.12-4.17 (m, 1H), 4.2-4.24 (m, 3H), 5.61-5.64 (d, 1H), 6.58-6.60 (t, 1H), 6.79-6.81 (d, 1H), 7.23 (s, 1H), 7.60-7.85 (b, 1H). MS (M+H, 350.1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C@@H:11]3[CH2:28][CH2:29][CH2:30][N:10]3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[N:22]1([CH2:21][CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH:3]=4)[CH2:9][N:10]4[CH2:30][CH2:29][CH2:28][C@H:11]43)=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Ic1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a high-pressure reaction vial was added cis-6-(3-iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (Example 32, 40.0 mg, 0.08 mmol), trimethylsilylacetylene (9.0 mg, 0.093 mmol), Pd(PPh3)2Cl2 (6.0 mg, 0.008 mmol), Cul (2.0 mg, 0.008 mmol), PPh3 (4.0 mg, 0.016 mmol), Et2NH (0.12 mL, 1.2 mmol), and DMF (0.1 mL). The sealed vial was placed in a 120° C. preheated oil bath for 30 min, cooled to rt, concentrated under a stream of nitrogen, and purified by reverse-phase HPLC to give 27.0 mg (47%) of the desired product as a TFA salt. MS: exact mass calcd for C31H42N2OSi, 486.3; m/z found, 487.6 [M+H]+. 1H NMR (acetone-d6): 7.46 (m, 2H), 7.36 (m, 2H), 6.97 (d, J=2.5, 1H), 6.80 (dd, J=2.6, 8.7, 1H), 6.65 (d, J=8.7, 1H), 4.92 (m, 1H), 4.63 (m, 1H), 4.14 (t, J=6.0, 2H), 3.95 (m, 1H), 3.66 (m, 3H), 3.51 (m, 1H), 3.41 (m, 1H), 3.31 (m, 2H), 2.95 (m, 3H), 2.32 (m, 5H), 1.89 (m, 5H), 1.50 (m, 1H), 0.22 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:3]=1.[H-].[Na+].[CH:21]1([CH2:25][CH:26](OS(C(F)(F)F)(=O)=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH:26]([CH2:25][CH:21]3[CH2:22][CH2:23][CH2:24]3)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:12](=[O:18])[CH:11]=2)[CH:3]=1
Reactant: CCOC(=O)C(CC1CCC1)OS(=O)(=O)C(F)(F)F
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(CC1CCC1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
122 mg (purity 87%, 0.41 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile in the presence of 1.3 eq. of sodium hydride and 161 mg (0.53 mmol, 1.3 eq.) of ethyl 3-cyclobutyl-2-{[(trifluoromethyl)sulphonyl]oxy}propanoate (racemate) were reacted at RT according to General 4E. The crude product was purified by flash chromatography (KP-SIL, cyclohexane/ethyl acetate 15-33%). Yield: 140 mg (82% of theory)