Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>ClCCl.N1C=CC=CC=1>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)CCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCl)Nc1ccccc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 68.6 %

Procedure:
To a solution of 2-anilinoaniline (4.0 g) in a mixture of dichloromethane (20 ml) and pyridine (6.87 g) was dropwise added 4-chlorobutyryl chloride (4.29 g) at 8° C. during a period of 16 minutes. The mixture was stirred at the same temperature for 40 minutes and then diluted with ice-water. The mixture was extracted twice with dichloromethane. The combined extract was washed with 1 N hydrochloric acid and water in turn and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a crystalline residue of 4-chloro-N-(2-anilinophenyl)butyramide (4.3 g).
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[C:16]2=[O:22])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([CH:28]=[CH:29][C:30](O)=[O:31])=[CH:26][C:25]=1[F:35].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:23][C:24]1[CH:34]=[CH:33][C:27](/[CH:28]=[CH:29]/[C:30]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[C:16](=[O:22])[CH:17]2[CH3:21])=[O:31])=[CH:26][C:25]=1[F:35]
Reactant: CC1NCCN(CCCN2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C(O)C=Cc1ccc(Cl)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(Cl)c(F)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2,5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 38; 0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 4-chloro-3-fluorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=464.3 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][C:2]=1[OH:12].N12CCCN=C1CCCCC2.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(C)C>[CH2:24]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[C:2]([OH:12])[CH:3]=[CH:4]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2cccc(O)c2n1
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: Oc1ccc2cccc(OCc3ccccc3)c2n1
Yield: 77.4 %

Procedure:
This was prepared by a slight modification of the procedure of Guo et al, Tet Lett, 1999, 40, 6999. To a stirred solution of 2,8-quinolinediol (4.97 g, 30.84 mmol) and 1,8-diazabicylo[5.4.0]undec-7-ene (DBU) (40.2 mmol, 6 mL) in isopropyl alcohol (60 mL) was added benzyl bromide (3.7 mL, 30.84 mmol). The solution was heated at reflux overnight. The reaction mixture was allowed to cool and then concentrated in vacuo. The resulting residue was diluted with CH2Cl2 and washed with 0.5 N NaOH, 10% HCl and water and dried over Na2SO4. Concentration provided 6 g (77%) of a tan solid, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[C:34]1([CH2:40][CH2:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([NH:42][CH2:41][CH2:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NCCc4ccccc4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and phenylethylamine. ES-MS m/e (%): 490 (M+H+, 100).
Reaction SMILES: C(N)C.[CH3:4][Si:5]([C:8]#[CH:9])([CH3:7])[CH3:6].[CH2:10]([S:17]/[C:18](/I)=[CH:19]\[CH:20]=[C:21](/[S:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)\[Sn:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>C1C=CC=CC=1.[Cu]I.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>[CH2:42]([S:41]/[C:21](/[Sn:22]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:20]\[CH:19]=[C:18](\[S:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:9]#[C:8][Si:5]([CH3:7])([CH3:6])[CH3:4])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: I/C(=C/C=C(\SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)SCc1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCN
Solvent: c1ccccc1
Solvent: ClCCl
Product: C[Si](C)(C)C#C/C(=C\C=C(/SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 38 h
Yield: 86.3 %

Procedure:
A mixture of EtNH2 (1 mL) and trimethylsilylethyne (32 mL, 0.23 mmol) were added to a solution of 5 (0.148 g, 0.190 mmol), CuI (1.81 mg., 0.0095 mmol) and (Ph3P)2PdCl2 (6.67 mg, 0.0095 mmol) in benzene (3 mL) under argon. The resulting yellow-green solution was stirred at room temperature for 38 h, and then concentrated in vacuo. The residue was mixed with ether (20 mL) and water (5 mL), the layers were separated and the aqueous layer was extracted by ether (2×10 mL). The combined ether layers were washed with NH4Cl solution (2×25 mL) and water (10 mL), dried (MgSO4), and concentrated in vacuo. Flash column chromatography (1:6 CH2Cl2 :hexanes) of the dark, oily residue gave 7 as a yellow solid (122 mg, yield 86%): mp 122°-123° C.; 1H NMR δ 6.9-7.8 (m, 27 H), 4.06, 37.27, 0.03; Anal. Calcd for C41H40S2SiSn, C, 66.21; H, 5.42. Found, C, 66.42; H, 5.55.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].O>N1C=CC=CC=1>[CH2:12]([O:20][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19]
Reactant: C#CCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: C#CCCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 7.5 °C
Reaction time: 20 h
Yield: 85.8 %

Procedure:
To an ice-cooled solution of p-toluenesulfonyl chloride (17.4 g, 91.3 mmol) in pyridine (30 ml), 7-octyn-1-ol (9.6 g, 76.1 mmol) was added dropwise, and stirred at 5-10° C. for 20 hours. The reaction mixture was added with water (15 ml), stirred, then poured into water (500 ml), and extracted with ether (500 ml). The ether layer was washed with cold 1N-hydrochloric acid, saturated aqueous sodium hydrogencarbonate and water, dried over magnesium sulfate, and concentrated under reduced pressure to afford 18.3 g of 7-octynyl-p-toluenesulfonate (yield; 85.7%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:18]=[C:19]([NH:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:20]2[N:21]([C:23]([CH3:26])=[N:24][N:25]=2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](O)(=O)C.C=O>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:18]=[C:19]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[C:20]2[N:21]([C:23]([CH3:26])=[N:24][N:25]=2)[N:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1nnc2c(NC3CCNCC3)cc(-c3cc4ccccc4n3Cc3ccccc3)nn12
Agent: C=O
Solvent: C1CCOC1
Product: Cc1nnc2c(NC3CCN(C)CC3)cc(-c3cc4ccccc4n3Cc3ccccc3)nn12
Reaction time: 2 h

Procedure:
[6-(1-Benzyl-1H-indol-2-yl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-piperidin-4-yl-amine (10 mg; 0.02 mmol) was dissolved in 300 μl THF, treated with glacial acetic acid (3 μl 0.05 mmol) and formaldehyde (7 μl; 0.09 mmol). At least was added STAB (6 mg; 0.03 mmol) and all stirred for 2 hours. The crude reaction mixture was purified by reversed phase under basic conditions.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[NH:9][N:8]=1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.N>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:7]([NH2:6])[N:8]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH3:16])[CH:18]=[CH:19]3)[N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1ccc2cc(-n3nc(C(C)(C)C)cc3N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a mixed solvent of dimethylformamide (8 mL) and pyridine (0.47 mL) were added 3-amino-5-tert-butylpyrazole (810 mg), N-methylindol-5-boronic acid (780 mg), copper (II) acetate (790 mg) and molecular sieves (400 mg). The reaction mixture was stirred overnight at room temperature. The reaction mixture was added with 10% aqueous ammonia and filtered through Celite®. The filtrate was added with ethyl acetate and separated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=7:3→1:1→1:4) to give the titled compound (577 mg) having the following physical data.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][CH2:19][C:20]2[C:25]([N+:26]([O-])=O)=[CH:24][N:23]=[C:22]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[CH2:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:26][C:25]1[C:20]([CH2:19][NH:18][CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:10])=[CH:21][C:22]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:23][CH:24]=1
Reactant: [H][H]
Reactant: CC(C)(C)CCNC(=O)CC(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)CCNC(=O)CC(NCc1cc(Oc2ccccc2)ncc1N)C1CCCCC1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
In a Parr bottle 10% Pd/C (0.42 g) was added and cooled to −78° C., then a solution of 3-cyclohexyl-N-(3,3-dimethyl-butyl)-3-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-propionamide (0.42 g, 0.87 mmol) in ethyl acetate (5 mL) and ethanol (20 mL) was added. The resulting mixture was subjected to hydrogen atmosphere and shaken for 3.5 h. The hydrogen was purged with nitrogen, then the reaction mixture was filtered (glass fiber filter paper) and the solvent was evaporated under reduced pressure to yield the title compound as a residue.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:15][C:16]1[S:20][C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[NH2:26])=[N:18][CH:17]=1>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:26][C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:19]3[S:20][C:16]([CH3:15])=[CH:17][N:18]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1cnc(-c2sccc2N)s1
Reactant: O=C(O)Cc1cccc2cnccc12
Product: Cc1cnc(-c2sccc2NC(=O)Cc2cccc3cnccc23)s1

Procedure:
The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid and 2-(5-methylthiazol-2-yl)thiophen-3-amine using Protocol A. Method[7], MS(ESI) 366.0 [M+H], Retention time=3.157 min; 1H-NMR (300 MHz, CDCl3) δ 11.24 (s, 1H), 9.67 (s, 1H), 8.57 (d, J=6.6 Hz, 1H), 8.30 (d, J=6.6 Hz, 1H), 8.26 (d, J=8.24 Hz, 1H), 8.08-8.04 (m, 2H), 7.96-7.91 (m, 1H), 7.20 (d, J=5.5 Hz, 1H), 6.97 (d, J=1.1 Hz, 1H), 4.31 (s, 2H), 2.43 (d, J=1.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.C[Si]([C:26]#[C:27][Sn](CCCC)(CCCC)CCCC)(C)C>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[C:26]#[CH:27]
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: C#Cc1cc(-c2ccc(O)c(F)c2)nc2c(Cl)cc(O)cc12
Yield: 73 %

Procedure:
This compound was prepared from 45a following a combination of method J using (trimethylsilylethynyl)tributyltin and method L. Yellow solid; Yield: 73%; mp 210° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 5.06 (s, 1H), 7.09 (dd, J=8.9, 8.8 Hz, 1H), 7.45 (d, J=2.6 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 8.00 (dd, J=8.5, 1.7 Hz, 1H), 8.12 (dd, J=12.9, 2.2 Hz, 1H), 8.26 (s, 1H), 10.34 (s, 1H), 10.60 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.30 (dd, J=13.2, 9.3 Hz); MS (ESI) m/z 312/314 ([M−H]−), 314/316 ([M+H]+); Anal. Calcd for C17H9ClFNO2: C: 65.09, H: 2.89, N: 4.46. Found: C: 64.86, H: 3.14, N: 4.05.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)(O)[O-].[Na+]>CO.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1Cl
Yield: 81 %

Procedure:
To 2.0 g of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 50 mL of methanol was added 1.9 g of 2,4-dichloroaniline. After refluxing the reaction under an inert atmosphere for 2 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/hexanes. Drying in vacuo yielded 2.6 g (80%) of 4-(2,4dichloro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile as yellow needles: melting point 206-208° C.; mass spectrum (m/e): M+H 332.8.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([C:22]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:24][CH2:23]4)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:9]([F:31])[CH:8]=1.Cl>C1COCC1>[F:31][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[C:13]1[S:14][C:15]2[CH:21]=[C:20]([C:22]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:24][CH2:23]3)[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH:2]=[O:1]
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccn4)CC3)cc2s1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3ccc(C4(c5ccccn5)CC4)cc3s2)c(F)c1
Temperature: 25 °C

Procedure:
2-(4-(1,3-Dioxan-2-yl)-2-fluorophenyl)-6-(1-(pyridine-2-yl)cyclopropyl)benzo[d]-thiazole (38 mg, 0.088 mmol) was stirred in THF (1 mL) and 5 N HCl (aq., 0.2 mL) at 50° C. for 2 h. The reaction mixture was cooled to RT, neutralized with satd. NaHCO3, and extracted with EtOAc three times. The organic extracts were dried (MgSO4) and concentrated to give 3-fluoro-4-(6-(1-(pyridine-2-yl)cyclopropyl)benzo[d]thiazol-2-yl)benzaldehyde as a yellow solid. MS (ESI) m/z: Calculated: 374.1; Observed: 375.0 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:30])C=C.C([O-])(O)=O.[Na+]>CC#N>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Br:30])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCCO)cc1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCCBr)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g) and 1,1′-carbonyldiimidazole (9.0 g, 55.50 mmol) in CH3CN (200 mL) was stirred at room temperature for 1.5 h. Allyl bromide (20 mL) was added and the reaction mixture was heated under reflux for 20 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3 was added. The aqueous solution was washed with EtOAc (3×) and the organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided the title compound of Preparation 4.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:10]1[C:2]([CH3:1])=[C:3]([C:7]([CH3:12])=[CH:8][C:9]=1[CH3:11])[C:4]([OH:6])=[O:5])([O-:15])=[O:14]
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Reactant: O=[N+]([O-])O
Product: Cc1cc(C)c([N+](=O)[O-])c(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a suspension of 2,4,6-trimethylbenzoic acid (4.6 g, 28 mmol) in 70% HNO3 (85 mL) conc. H2SO4 (5 mL). was added dropwise at RT. The brown reaction mixture was stirred for 1 h, poured into ice-water (500 mL). The product was extracted into ethyl acetate, the extract was washed with water, dried over MgSO4 and concentrated to give 3-nitro-2,4,6-trimethylbenzoic acid as a yellow solid (6.7 g, 94%).
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][C:10]2[C:15]([CH:16]=[O:17])=[CH:14][C:13]([O:18][CH3:19])=[N:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:22]=[N:23][N:24]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:25]=1B(O)O.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.CN(C=O)C>[CH3:19][O:18][C:13]1[CH:14]=[C:15]([C:10]([O:9][CH2:8][C:7]2[C:2]([C:25]3[N:24]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)[N:23]=[CH:22][C:21]=3[CH3:20])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][N:12]=1)[CH:16]=[O:17]
Reactant: Cc1cnn(C2CCCCO2)c1B(O)O
Reactant: COc1cc(C=O)c(OCc2cccnc2Br)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: CN(C)C=O
Product: COc1cc(C=O)c(OCc2cccnc2-c2c(C)cnn2C2CCCCO2)cn1
Temperature: 125 °C
Yield: 86.9 %

Procedure:
To a mixture of 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (100 mg, 0.31 mmol, 1 equiv), 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-ylboronic acid (98 mg, 0.47 mmol, 1.5 equiv), Pd(PPh3)4 (70 mg, 0.06 mmol, 0.2 equiv), K2CO3 (171 mg, 1.24 mmol, 4 equiv) in a 5 mL microwave tube was added DMF (2 mL). The mixture was heated 30 min at 125° C. in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((2-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (110 mg, 87%) as a colorless oil. LRMS (M+H+) m/z 409.2.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](=[N:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:4]([CH3:15])[C:3]=1[CH3:16].C1C(=O)N([Br:24])C(=O)C1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[S:6][C:5](=[N:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[N:4]([CH2:15][Br:24])[C:3]=1[CH3:16]
Reactant: Cc1c(Br)sc(=NC(=O)OC(C)(C)C)n1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: Cc1c(Br)sc(=NC(=O)OC(C)(C)C)n1CBr
Yield: 85.1 %

Procedure:
tert-Butyl (5-bromo-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)carbamate (2.9 g) obtained in Example 30b) was dissolved in 1,2-dichloroethane (50 mL). AIBN (0.1 g) and NBS (1.7 g) were added thereto at room temperature, and the mixture was mixed at 80° C. for 3 hours. The reaction solution was poured into an aqueous potassium carbonate solution. The mixture was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give tert-butyl (5-bromo-3-bromomethyl-4-methyl-1,3-thiazol-2(3H)-ylidene)carbamate (3.1 g) as a brown oily matter. The resulting compound and 1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (1.0 g) obtained in Example 3a) were dissolved in DMF (30 mL). Potassium carbonate (0.75 g) was added thereto and the mixture was mixed at 70° C. for 4 hours. The solvent was distilled off, and the residue was poured into water. The mixture was extracted with a mixed solution of chloroform-methanol, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a basic silica gel column to give the title compound (1.2 g) as a white powder.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][C:10](O)=[S:11])[CH:6]=[CH:5][CH:4]=1)#[N:2].ClC(OCC(C)C)=O.C([N:23](CC)CC)C.[NH4+]>C(OCC)(=O)C.C1COCC1>[C:1]([C:3]1[N:8]=[C:7]([CH2:9][C:10]([NH2:23])=[S:11])[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: N#Cc1cccc(CC(O)=S)n1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cccc(CC(N)=S)n1
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A mixture of (6-cyano-2-pyridyl)thioacetic acid (0.95 g, 4.89 mmol), isobutyl chloroformate (1.05 ml, 7.33 mmol), triethylamine (1.03 ml, 7.33 mmol) and THF (150 ml) was stirred under ice cooling condition for 2 hrs. 28% ammonium solution (100 ml) was added to the mixture, and the mixture was stirred under ice cooling condition for 2 hrs. The reaction mixture was combined with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated to give the titled compound (0.49 g, 52%) as pale yellow crystals
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH3:13][C:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]#[N:26])([CH3:16])[CH3:15]>C(O)C>[CH3:16][C:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][C:25]#[N:26])[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCNCC#N
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(N(CC#N)CCCNC(=O)OC(C)(C)C)c(=O)c1=O
Yield: 90.2 %

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.6 mL, 18 mmol) in absolute ethanol (90 mL) was treated with [3-(cyanomethylamino)propyl]carbamic acid 1,1-dimethylethyl ester (3.90 g, 18 mmol) in ethanol (30 mL) over 90 min. After 40 hours the reaction mixture was evaporated, dissolved in dichloromethane, preadsorbed onto silica gel, and purified by flash chromatography (7 cm diameter, gradient elution with 0-5% methanol in dichloromethane) to yield [3-[(cyanomethyl)-(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]propyl]carbamic acid 1,1-dimethylethyl ester as a yellow oil (5.48 g, 90%); IR (neat, cm-1): 3360, 1800; MS (+FAB): 282 (76), 238 (98), 158 (100); 1H NMR (CDCl3, 400 MHz): δ 4.81 (q, J=7 Hz, 2H), 4.75 (br s, NH), 4.45, 3.66 (s, 2H), 3.84, 3.60 (br m, 2H), 3.26-3.15 (m, 2H), 1.91 (p, J=6.5 Hz, 2H), 1.50 (t, J=7 Hz, 3H), 1.45 (s, 9H).