Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5](=O)[C:6]([OH:8])=[O:7])=[N+:2]=[N-:3].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[N:19]=[C:20]([NH:23][NH2:24])[S:21][CH:22]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]>C(O)(=O)C.C(O)C>[N:1]([CH2:4]/[C:5](=[N:24]\[NH:23][C:20]1[S:21][CH:22]=[C:18]([C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=2)[N:19]=1)/[C:6]([OH:8])=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(=O)C(=O)O
Reactant: NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Solvent: CCO
Solvent: CC(=O)O
Product: [N-]=[N+]=NC/C(=N\Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
KY-757 3-azido-2-oxopropanoic acid, KY-740 (100 mg, 0.77 mmol) in 5% acetic acid 162 ul was added in to solution of [4-(3,4-Dichloro-phenyl)-thiazol-2-yl]-hydrazine (0.2 gr, 0.77 mmol) in ethanol 2 ml. the reaction mixture was stirred at room temperature for 5 h. and then cooled to room temperature. The yellow solid was precipitated out, filtered and washed by water. Yield 0.1 gr (35%). MS+(ESI) m/z 371.91, calcd mass 371.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:40])=[CH:19][C:20]([CH3:39])=[C:21]([C:23]4[NH:38][C:26]5[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][C:25]=5[N:24]=4)[CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH3:40][C:18]1[CH:19]=[C:20]([CH3:39])[C:21]([C:23]2[NH:38][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:25]=3[N:24]=2)=[CH:22][C:17]=1[C:15]([N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1)=[O:16]
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 133.8 %

Procedure:
To a solution of tert-butyl 2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound 2.8, 100 mg, 0.17 mmol, 1.00 equiv, 90%) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature. After 2 h, the reaction mixture was concentrated under reduced pressure. The residue was taken up in dichloromethane and washed with sodium bicarbonate (aq., sat.). The organic phase was dried (Na2SO4) and concentrated under reduced pressure to yield 0.1 g (68%) of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(S(C)(=O)=O)cc4)c3)cnc2c1F
Yield: 6 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-methanesulfonylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-4′-methanesulfonylbiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (8 mg, 6%): m/z (ES+) 443 [MH+].
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][N:27](COC)[CH:28]=2)=[CH:12][C:11]=1[F:32])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[F:32][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)(=[O:8])=[O:9]
Reactant: COCn1cc([C@H]2CCCC[C@@H]2Oc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ccncn3)cc2C)cn1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCCC[C@@H]1c1cn[nH]c1
Yield: 99 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 147e by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S,2R)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (61.5 mg, 0.0983 mmol) prepared in Example 172a, triethylsilane (0.079 mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol (15 mL) and 6 M hydrochloric acid (5.0 mL), to yield the title compound (42.0 mg, 99%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[CH:3]([N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:4]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5]1.[CH2:25]([O:27][C:28]([C:30]#[C:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:29])[CH3:26]>CCO>[NH2:1][C:2](=[N:23][O:24]/[C:31](=[CH:30]/[C:28]([O:27][CH2:25][CH3:26])=[O:29])/[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:3]([N:11]([C:12]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:21])[CH3:22])[CH:4]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5]1
Reactant: CN(C(=O)OCc1ccccc1)C(C(N)=NO)C1CCC(CO)C1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)/C=C(/ON=C(N)C(C1CCC(CO)C1)N(C)C(=O)OCc1ccccc1)C(=O)OCC
Temperature: 23 °C
Reaction time: 48 h
Yield: 63.3 %

Procedure:
To benzyl 2-amino-2-(hydroxyimino)-1-(3-(hydroxymethyl)cyclopentyl)ethyl(methyl)carbamate (0.800 g, 1.78 mmol) in EtOH (40 mL) was added diethylacetylenedicarboxylate (0.428 ml, 2.67 mmol). The reaction mixture was stirred at 23° C. for 2 days. The solvent was removed in vacuo and the crude material purified on a Silica gel column (Biotage flash chromatography system), eluted with a gradient of ethyl acetate:hexane (1:5) to (1:1) to afford 0.570 g (52% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.42 (5 H, m), 5.17-5.25 (3 H, m), 4.12-4.40 (4 H, m), 3.55 (2 H, m), 2.83-2.94 (4 H, m), 2.70-2.75 (1 H, m), 2.17-2.09 (2 H, m), 1.82-2.00 (3 H, m), 1.21-1.342 (7 H, m). LCMS (+ESI, M+H+) m/z 506.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2=[N:6][C:7](=[S:9])[N:8]=[C:4]2[CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.Br[C:23]1([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]1[O:26][C:27](=[O:29])[CH3:28])O.[I-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[N:6]([C@@H:23]3[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]3[O:26][C:27](=[O:29])[CH3:28])[C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1
Reactant: S=C1N=c2cc(Cl)c(Cl)cc2=N1
Reactant: CC(=O)OC[C@H]1OC(O)(Br)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=S)[nH]c3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of dry 5,6-dichlorobenzimidazole-2-thione (3, 2.19 g 10 mmole), hexamethyldisilazane (4 ml) and (NH4)2SO4 (0.1 g) was heated at reflux temperature with stirring for 15 hr under anhydrous conditions. The clear brown reaction mixture was fractionated to remove unreacted HMDS under reduced pressure (water aspirator) to afford the disilylated compound. The silylated compound was mixed with 1-bromo-2,3,5-tri-O-acetyl-D-ribofuranose (from 3.5 g (11 mmole) of tetraacetylsugar) and sodium iodide (0.05 g). The mixture was then fused at 110° C. (oil bath temperature) with stirring for 45 minutes under reduced pressure. The reaction mixture which had been cooled to room temperature was dissolved in CHCl3. The CHCl3 solution was washed with a cold saturated aqueous sodium bicarbonate solution (100 ml×4) and then cold water (100 ml×4). The CHCl3 phase was dried over Na2SO4 and evaporated on a water bath (40° C.) to dryness to yield a syrup [5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl) benzimidazole-2-thione]. The syrup was dissolved in methanolic ammonia (methanol saturated with ammonia at 0° C., 100 ml) and allowed to stand at room temperature for 24 hours. After the methanolic ammonia had been removed at room temperature, a syrup remained which was triturated with cold water (30 ml). The solid material (2.548 g) which separated was collected by filtration and was applied to a flash column chromatography on silica gel with CH2Cl2 -MeOH (15:1) as eluant. Fractions were collected (25 ml each), and fractions containing the desired compound were combined and evaporated to obtain 53 which was crystallized from aq. EtOH. Overall yield 2.0 g, 57.0%, mp 241° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][C:31]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(C(F)(F)F)ccc1Cl
Yield: 3.8 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-5-(trifluoromethyl)phenylboronic acid (available from Combi-Blocks Inc.; 112 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-5′-trifluoromethyl-biphenyl-2-carboxylic acid (5 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 13.19 (br s, 1H), 8.59 (s, 1H), 8.50 (s, 1H), 8.28-8.36 (m, 2H), 8.10 (d, J=8.5 Hz, 1H), 7.71-7.82 (m, 4H), 7.52 (d, J=8.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[CH2:15][CH:10]([CH2:11][CH2:12]3)[C:9]=2[CH:16]=[CH:17][CH:18]([OH:26])[CH2:19][CH:20]([OH:25])[CH2:21][C:22](O)=[O:23])=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[CH2:15][CH:10]([CH2:11][CH2:12]3)[C:9]=2/[CH:16]=[CH:17]/[C@@H:18]2[O:26][C:22](=[O:23])[CH2:21][C@@H:20]([OH:25])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CC(O)CC(O)C=CC1=C(c2ccc(F)cc2)CC2CCC1C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: O=C1C[C@@H](O)C[C@H](/C=C/C2=C(c3ccc(F)cc3)CC3CCC2C3)O1
Reaction time: 4 h
Yield: 42.6 %

Procedure:
To a solution of 7-[3-(4-fluorophenyl)bicyclo[3.2.1]-oct-2-en-2-yl]-3,5-dihydroxyhept-6-enoic acid (1.28 g, 3.55 mmoles) in 15 ml anhydrous ether at 0°-5° C. was added dicyclohexylcarbodiimide (0.74 g, 3.55 mmoles). The mixture was stirred for 4 hours, filtered and the volatiles were removed in vacuo. Purification of the residue using silica gel and 60% hexanes in ethyl acetate as the eluent provided 0.518 g of the solid product. mp 123°-127° C.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[N:14]=[C:3]21.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36].CNC.CO>C(Cl)Cl.CO>[C:35]([NH:1][C:2]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[O:16])[N:14]=[C:3]21)(=[O:37])[CH3:36]
Reactant: NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reactant: CC(=O)Cl
Agent: CNC
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
To a stirred solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (25 mg, 0.067 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.05 mL) followed by acetyl chloride (0.05 mL). After 16 h at room temperature the reaction mixture was concentrated to give crude product which was dissolved in methanol (2 mL) and treated with 2M dimethylamine/methanol (0.5 mL). The resulting reaction mixture stirred at 60° C. for 2 h, cooled and purified by preparative HPLC to afford the title compound as a white solid (3 mg, 11% yield). 1H NMR (500 MHz, CDCl3) δ: 12.00 (s, 1H), 7.32-7.35 (m, 3H), 7.04-7.09 (m, 2H), 6.69 (s, 1H), 4.57 (d, 2H, J=5.8 Hz), 4.14 (d, 2H, J=3.66 Hz), 2.63-2.66 (m, 2H), 2.44-2.47 (m, 1H), 1.91-1.97 (m, 4H), 1.86 (s, 3H), 1.63-1.67 (m, 2H). LCMS (M+H)=415.29. HPLC purity: >95%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:7]=2[N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)[CH2:3][CH2:2]1.C1(N(C2N=C(C)ON=2)C)CC1.[CH:33]1([CH2:36][C@H:37]([NH2:44])[C:38]2[N:42]=[C:41]([CH3:43])[O:40][N:39]=2)[CH2:35]C1>>[CH:36]1([CH:37]([NH:44][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[C:18]4([CH2:19][O:20][CH2:21]4)[CH2:17][CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[N:11]=2)=[O:13])[C:38]2[N:42]=[C:41]([CH3:43])[O:40][N:39]=2)[CH2:33][CH2:35]1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Reactant: O=C(O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1
Agent: Cc1nc(N(C)C2CC2)no1
Product: Cc1nc(C(NC(=O)c2ccc(N3CCC34COC4)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(cyclopropylmethoxy)-5-(6-oxa-1-azaspiro[3.3]heptan-1-yl)picolinic acid (Example 234 b) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can e.g. be prepared in a similar manner than (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials. MS (EI): m/e=426.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=1[N+:18]([O-])=O)[CH3:2].B.C1COCC1.O.C1COCC1>C1COCC1>[NH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[C:11]([NH2:18])[CH:12]=1
Reactant: CCOc1ccccc1-c1ccc(C#N)cc1[N+](=O)[O-]
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccccc1-c1ccc(CN)cc1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2′-ethoxy-2-nitrobiphenyl-4-carbonitrile (500 mg, 1.86 mmol) in THF (80 mL) was added a solution of BH3.THF (5.6 mL, 10% wt. in THF, 5.6 mmol) at 0° C. over 30 min. The reaction mixture was stirred at 0° C. for 3 h and then at room temperature for 15 h. The reaction solution was chilled to 0° C., and a H2O/THF mixture (3 mL) was added. After being agitated at room temperature for 6 h, the volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and extracted with 1N HCl (2×100 mL). The aqueous phase was basified with 1N NaOH solution to pH land extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (50 mL), dried over Na2SO4, filtered, and evaporated. After drying under vacuum, 4-aminomethyl-2′-ethoxy-biphenyl-2-ylamine was isolated as a brown oil (370 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ 7.28 (dt, J=7.2 Hz, J=1.8 Hz, 1H ), 7.09 (dd, J=7.2 Hz, J=1.8 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.96 (dt, J=7.2 Hz, J=0.9 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.66 (d, J=1.2 Hz, 1H), 6.57 (dd, J=7.5 Hz, J=1.5 Hz, 1H), 4.29 (s, 2H), 4.02 (q, J=6.9 Hz, 2H), 3.60 (s, 2H), 1.21 (t, J=6.9 Hz, 3H); HPLC ret. time 1.54 min, 10-100% CH3CN, 5 min gradient; ESI-MS 243.3 m/z (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[C:5]([Cl:24])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:35]([CH3:36])[C:34](=[O:37])[CH2:33][CH2:32][CH2:31][C:30]=2[CH:38]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[N:7][C:2]([NH:25][C:26]2[CH:27]=[CH:28][C:29]3[N:35]([CH3:36])[C:34](=[O:37])[CH2:33][CH2:32][CH2:31][C:30]=3[CH:38]=2)=[N:3][CH:4]=1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4C(N)=O)n3)ccc21
Temperature: 120 °C
Yield: 69.7 %

Procedure:
A microwave vessel was charged with 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-benzamide (50.0 mg, 0.136 mmol), 7-amino-1-methyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (31.6 mg, 0.166 mmol), 10-camphorsulfonic acid (3.5 mg, 0.015 mmol) and isopropyl alcohol (2 mL). This mixture was heated at 120° C. for 20 minutes in a microwave reactor (sealed vessel). After quenching with saturated aqueous NaHCO3 solution (2 mL), the resulting precipitate was collected by filtration, successively washed water (5×2 mL) and ether (2×1 mL) to afford product as a yellow powder (49.5 mg, 70%) that had the following properties: mp: 288-290° C.; LC/MS (ESI+): 522 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 11.29 (s, 1H), 9.45 (s, 1H), 8.46 (d, J=8.0, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.52 (d, J=8.9, 1H), 7.32 (s, 1H), 7.20 (d, J=8.6, 1H), 7.09 (d, J=9.4, 1H), 3.77 (m, 4H), 3.25 (s, 3H), 3.15 (m, 4H), 2.60 (m, 2H), 2.20-2.10 (m, 2H), 2.10-2.00 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:27])=[C:18]([C:19]4[CH:20]=[N:21][C:22]([O:25]C)=[CH:23][CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])(O)=O.[Na+]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:27])=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[N:21][CH:20]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2c(C)nc3sc(-c4ccc(OC)c(OC)c4)nn23)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(-c2nn3c(-c4ccc(O)nc4)c(C)nc3s2)cc1OC
Temperature: 25 °C
Yield: 18.6 %

Procedure:
A solution of 2-(3,4-dimethoxy-phenyl)-5-(6-methoxy-pyridin-3-yl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (0.028 g, 0.073 mmol, 1 eq) in 25% HCl (0.75 mL) was subjected to microwave irradiation (95° C., 2 h, 200 W). The reaction mixture was cooled to RT, neutralized with NaHCO3 (sat. sol) and extracted with EtOAc and subsequently with CH2Cl2/MeOH (9:1). The organic phase was dried (MgSO4), filtered and concentrated. The crude (0.007 g) was purified by preparative HPLC (RP-C18, ACN/water) affording the desired product (yellowish solid, 0.005 g, 19%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=3.94 min, [M+H]+ m/z 369.1; 1H NMR (300 MHz, CDCl3) δ/ppm 12.94 (s, 2H), 7.82 (dd, J=9.5, 2.5, 1H), 7.72 (d, J=2.2, 1H), 7.34 (dd, J=8.3, 2.0, 1H), 7.30 (d, J=2.0, 1H), 6.88 (d, J=8.4, 1H), 6.69 (d, J=9.5, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11])=[O:3].[CH2:12]([C:14]([CH2:16][CH3:17])=O)[CH3:13].N1CCCC1.C1(C)C=CC=CC=1>O>[CH2:12]([C:14]1([CH2:16][CH3:17])[CH2:1][C:2](=[O:3])[C:4]2[C:5](=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=2)[O:11]1)[CH3:13]
Reactant: CCC(=O)CC
Reactant: CC(=O)c1ccc(O)cc1O
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNC1
Product: CCC1(CC)CC(=O)c2ccc(O)cc2O1
Reaction time: 24 h
Yield: 64 %

Procedure:
1.52 g (10.0 mmoles) of resacetophenone are dissolved in 1.20 g (14.0 mmoles) of diethyl ketone, then 1.42 g (20.0 mmoles) pyrrolidine [prepared according to the method of H. J. Kabbe in Synthesis, 886 (1978)] are added thereto. The reaction mixture is allowed to stand at room temperature for 24 hours, then 40 ml of toluene are added. The reaction mixture is boiled under reflux for 10 hours by using a water separator. Then it is cooled back, washed subsequently with 10% hydrochloric acid and water, thereafter it is dried and evaporated to obtain 1.41 g of 2,2-diethyl-7-hydroxy-4-chromanone in the form of a pale yellow viscous oil which crystallizes on standing.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:22][O:23][C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26][CH3:27])=[CH:7][CH:6]=1.[OH-].[Na+].Cl>CO>[CH3:28][C:25]([CH3:29])([CH2:26][CH3:27])[C:24](=[O:30])[O:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:31])[C:3]([OH:32])=[O:2])=[CH:6][CH:7]=1
Reactant: CCC(C)(C)C(=O)OCc1cccc(C)c1OCCOc1ccc(C(=O)C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)(C)C(=O)OCc1cccc(C)c1OCCOc1ccc(C(=O)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a solution of 4-[[2-[2-[(2,2-dimethyl-1 -oxobuyloxy)methyl]-6-methylphenoxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.554 g) in methanol (10 mL) was added aqueous 1N sodium hydroxide (2.5 mL). After 30 minutes at 50° C., the reaction was acidified with 1N hydrochloric acid (2 mL) and extracted with dichloromethane. The organic phase was washed with brine and evaporated to provide 0.47 g of 4-[[2-[2-[(2,2-dimethyl-1-oxobuyloxy) methyl]-6-methylphenoxy]ethyl]oxy]-alpha-oxobenzeneacetic acid (2:1) hydrate as a clear oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][CH2:11][S:12][C:13]([F:16])([F:15])[F:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[F:35][C:36]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:37]=1[NH2:38]>C1COCC1.N#N>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:17](=[O:19])[NH:38][C:37]1[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:36]=1[F:35])[CH2:10][CH2:11][S:12][C:13]([F:14])([F:15])[F:16])([CH3:5])([CH3:6])[CH3:7]
Reactant: Nc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CCSC(F)(F)F)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(CCSC(F)(F)F)C(=O)Nc1ccc(F)cc1F
Yield: 54.2 %

Procedure:
N-Boc-trifluoromethionine (212 mg, 0.851 mmol) was dissolved in dry THF in the presence of N2, and the temperature was adjusted to −78° C. Subsequently, N-methylmorpholine (0.11 ml, 1.000 mmol) was added thereto, and the mixture was stirred. Two minutes later, isobutyl chloroformate (0.13 ml, 0.999 mmol) was added thereto, and the mixture was stirred for 2 minutes. Finally, 2,4-difluoroaniline (0.10 ml, 0.982 mmol) was added thereto. TLC was performed to confirm disappearance of the starting compound, and the solid matters were filtered, followed by distillation of THF under reduced pressure. The residue was purified by column chromatography (Hex:AcOEt=80:20), thereby the product (191 mg, 54%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8](I)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([Cu])#[N:14]>CC(N(C)C)=O>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:13]#[N:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: N#C[Cu]
Reactant: COC(=O)c1c(I)ccnc1Cl
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(C#N)ccnc1Cl
Yield: 34.5 %

Procedure:
A solution of methyl 2-chloro-4-iodonicotinate (3.20 g, 10.76 mmol) and cyanocopper (0.963 g, 10.76 mmol) in DMA (40 mL) was stirred at 140° C. overnight. Following reaction, the mixture was filtered through Celite and the filtrate was diluted with H2O and EtOAc. The aqueous phase was extracted with EtOAc. The organic phases were combined, washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 (Hexane/EtOAc=10/1) to give the title compound as a white solid (730 mg, 34.5%). 1H NMR (500 MHz, CDCl3) δ ppm 4.07 (s, 3H), 7.57 (d, J=5.37 Hz, 1H), 8.66 (d, J=4.88 Hz, 1H).