Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Br[C:15]1[S:19][C:18]([C:20]2([OH:24])[CH2:23][CH2:22][CH2:21]2)=[N:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[S:19][C:18]([C:20]3([OH:24])[CH2:23][CH2:22][CH2:21]3)=[N:17][CH:16]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1cc(B(O)O)cc([N+](=O)[O-])c1
Reactant: OC1(c2ncc(Br)s2)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cc(-c2cnc(C3(O)CCC3)s2)cc([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 91.9 %

Procedure:
To a solution of commercially available (3-amino-5-nitrophenyl)boronic acid (18 g, 99 mmol) and Intermediate 1 (25.5 g, 109 mmol) in DME (360 mL) were added tetrakis(triphenyl-phosphine)palladium(0) (5.72 g, 4.95 mmol) and 2M Na2CO3(aq) (148 mL, 297 mmol), and the mixture was degassed and then heated to 85° C. for 5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (500 mL) and filtered through Celite (ethyl acetate rinse). The filtrate was washed with brine (300 mL), dried (Na2SO4) and concentrated in vacuo. The impure material was split into two batches, and each purified by Chromatography on silica gel (70:30 to 0:100 hexanes:ethyl acetate) then the product fractions from the two purifications were combined and concentrated in vacuo to provide 26.53 g (91 mmol, 92%) of 1-[5-(3-amino-5-nitrophenyl)-1,3-thiazol-2-yl]cyclobutanol as a green solid. MS ESI: [M+H]+ m/z 292.0. 1H NMR (DMSO-d6): δ 8.15 (1H, s), 7.54 (1H, s), 7.33 (1H, s), 7.14 (1H, s), 6.58 (1H, s), 6.00 (2H, s), 2.56-2.47 (2H, m), 2.39-2.29 (2H, m), 1.95-1.83 (2H, m).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21]1>[OH-].[K+].CCO>[O:20]1[CH:24]=[CH:23][C:22]([CH:25]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])=[CH:21]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccoc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccoc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 69.8 %

Procedure:
According to the method of Example 8, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.20 g, 0.78 mmol) was reacted with 3-furaldehyde (0.083 g, 0.86 mmol) in 2 mL of 4% KOH in EtOH for 48 hours at room temperature to afford 0.182 g (70%) of the title compound, mp 116-117° C.: APCI-MS m/e 335.3 (M++1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][CH2:14][CH:15](O)[CH2:16][F:17].[NH2:19][C:20]1[CH:24]=[CH:23][O:22][N:21]=1>>[F:13][CH2:14][CH:15]([CH2:16][F:17])[O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:19][C:20]1[CH:24]=[CH:23][O:22][N:21]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: OC(CF)CF
Reactant: Nc1ccon1
Product: FCC(CF)Oc1ccc2ncnc(Nc3ccon3)c2c1

Procedure:
The compound of Example 28 was manufactured by the same method as in Example 22, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-hydroxy-quinazoline, 1,3-difluoro-2-propanol and 3-aminoisoxazole.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[N:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:54][C:51]4[CH:52]=[CH:53][N:48]=[CH:49][CH:50]=4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: Nc1ccncc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2ccncc2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl )-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with pyridin-4-ylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H46Cl2N7O3 [(M+H)+] 742.3034, observed 742.3036.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].CCO.[OH-].[Na+:36].CC(O)C>O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:36]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(C)O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 63.3 %

Procedure:
Into a 100 ml flask were placed fluvastatin methyl ester (3.0 g), EtOH (7.5 ml) and a solution of NaOH (0.28 g) in water (0.75 ml). The mixture was heated to reflux for two h, propan-2-ol was added (58 ml) and the mixture was cooled to room temperature and stirred over night. The product was isolated by filtration under nitrogen, washed with propan-2-ol (50 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 1.92 g (62.8%) of fluvastatin sodium crystal Form IX.
Reaction SMILES: O.O.O.O.O.O.O.O.O(Cl)Cl.[Zr:12].O.O.C(O)(=O)C(O)=O.[P:21](=[O:25])([OH:24])([OH:23])[OH:22]>O.[Hf]>[P:21]([O-:25])([O-:24])([O-:23])=[O:22].[Zr+4:12].[P:21]([O-:25])([O-:24])([O-:23])=[O:22].[P:21]([O-:25])([O-:24])([O-:23])=[O:22].[P:21]([O-:25])([O-:24])([O-:23])=[O:22].[Zr+4:12].[Zr+4:12]
Reactant: O=P(O)(O)O
Reactant: [Zr]
Agent: [Hf]
Agent: ClOCl
Agent: O=C(O)C(=O)O
Solvent: O
Product: O=P([O-])([O-])[O-]
Product: [Zr+4]

Procedure:
0.272 mol of zirconium oxychloride octahydrate containing 2.0% of hafnium was dissolved in 850 ml of deionized water, and thereafter, 0.788 mol of oxalic acid dihydrate was dissolved therein. 0.57 mol of phosphoric acid was added to the solution under stirring. The solution was stirred and refluxed for 8 hours. After cooling, the obtained precipitate was well washed with water, and thereafter dried at 105° C. to obtain a zirconium phosphate. As a result of measurement of the obtained zirconium phosphate, it was confirmed to be a layered zirconium phosphate.
Reaction SMILES: [H-].[Na+:2].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[H][H]>C1COCC1>[CH3:10][O:9][C:3](=[O:8])/[CH:4]=[C:5](/[O-:6])\[CH3:7].[Na+:2]
Reactant: [H][H]
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C(\C)[O-]

Procedure:
60 g of a 30% strength sodium hydride suspension in mineral oil (744 mmol of NaH) are suspended in 250 ml of dry THF in an inert gas atmosphere. 86.4 g (744 mmol) of methyl acetoacetate in 200 ml of THF are slowly added dropwise, the resulting hydrogen being led directly into the waste air. After dropwise addition has taken place, the mixture is stirred at reflux for half an hour and then cooled. The solvent is stripped off in vacuo and the residual solid is washed with diethyl ether.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[C:3][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCBr
Reactant: C#CCOC1CCCCO1
Product: CCCCCCCCCCCCC#CCOC1CCCCO1
Yield: 79.6 %

Procedure:
Alkylation of 2-(prop-2-ynyloxy)tetrahydro-2H-pyran (15.5 g, 110.71 mmol) with 1-bromododecane (34.0 g, 132.04 mmol) as described above gave 2-(pentadec-2-ynyloxy)tetrahydro-2H-pyran (27.2 g, 80%) which was used without further purification. TLC: 10% EtOAc/hexanes, Rf≈0.5.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:11][CH2:12][CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:18]O>>[OH:1][C:2]1[C:3]([CH2:11][CH2:12][CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: CCCc1c(O)cccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCCc1c(O)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 35 h
Yield: 87 %

Procedure:
Cool a solution of 3-hydroxy-2-propyl-benzoic acid (59.79 g, 332 mmol) in MeOH (598 mL) to −10° C. and add thionyl chloride (36.26 mL, 497.1 mmol) using a syringe pump over 35 min. Allow the mixture to warm to ambient temperature while stirring over 35 h. Concentrate the mixture in vacuo and dilute the residue with methyl-tert-butylether (360 mL). Concentrate the resultant mixture in vacuo to dryness to yield the title compound (64.4 g, 87%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.38 (dd, J=8.0, 0.8 Hz, 1H); 7.10 (t, J=8.0 Hz, 1H); 6.93 (dd, J=8.0, 0.8 Hz, 1H); 5.1 (bs, 1 H); 3.89 (s, 3H); 2.98 (m, 2H), 1.61 (m, 2H); 1.00 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][NH:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[F:1][C:2]([F:14])([F:15])[CH2:3][NH:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(CNCC(F)(F)F)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NCc1ccc(CNCC(F)(F)F)cc1
Yield: 49 %

Procedure:
Dissolve 4-[(2,2,2-trifluoroethylamino)-methyl]-benzonitrile (633 mg, 2.955 mmol) in methanol (22 mL). Add cobalt(II) chloride hexahydrate (1.41 g, 5.91 mmol) and stir for 20 min. Carefully add sodium borohydride (1.12 g, 29.55 mmol) in small batches and stir the mixture overnight. Quench the mixture with water and filter through celite, washing filtercake with chloroform:methanol:concentrated NH4OH (80:18:2). Concentrate the filtrate in vacuo, and partition the residue between water and chloroform. Extract the aqueous phase three times with chloroform iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g, pre-packed cartridge) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15 over 5 min, 4:1; 50 mL/min) to obtain the title compound (316 mg, 49%). MS (ES+) m/z: 219 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].C(OC(=O)CO[C:31]1[C:40]2CCCCC=2C(S)=C[CH:32]=1)C.ClC1C=C(C=CC=1Cl)C=O>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[C:8]2[CH2:23][CH2:40][CH2:31][CH2:32][C:9]=2[C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[Cl:22])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(S)c2c1CCCC2
Reactant: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)cc1C
Agent: O=Cc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)c2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 10.4, using compound 22.3 and 3,4-dichlorobenzaldehyde as the starting materials. 1H NMR (300 MHz) (CDCl3) δ 9.84 (1H, s); 7.82 (1H, d, J=1.8 Hz); 7.49 (1H, dd, J=1.8, 8.4 Hz); 7.40 (1H, d, J=8.4 Hz); 6.63 (1H, d, J=8.4 Hz); 6.59 (1H, d, J=8.0 Hz); 4.70 (2H, s); 4.30 (2H, q, J=7.0 Hz); 2.82-2.70 (4H, m); 1.77-1.70 (4H, m); 1.32 (3H, t, J=7.0 Hz).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13](Br)[CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1([CH3:29])[CH2:25][CH2:24][C:23](B(O)O)=[CH:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:23]2[CH2:24][CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21][CH:22]=2)[CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)CCc1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(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: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(CCS(=O)(=O)NC(C)(C)C)ccc2N)CC1
Temperature: 80 °C
Yield: 64.8 %

Procedure:
A solution of 380 mg (1.13 mmol) of 2-(4-amino-3-bromo-phenyl)-ethanesulfonic acid tert-butylamide (as prepared in Example 47, step (a)) in toluene (10 mL) and EtOH (5 mL) was treated with 321 mg (1.36 mmol) of 4,4-dimethylcyclohex-1-enylboronic acid and 4.53 mL (9.06 mmol) of 2.0 M aqueous Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 131 mg (0.113 mmol) of Pd(PPh3)4, and heated to 80° C. for 19 h. The mixture was diluted with EtOAc (30 mL) and washed with water (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1% MeOH—CH2Cl2 afforded 267 mg (64%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C20H32N2O2S, 365.2 (M+H), found 365.2.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.[NH:20]1[CH:24]=[C:23]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[N:22]=[CH:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>C1COCC1.C(OCC)(=O)C>[CH:28]([O:27][C:25]([C:23]1[N:22]([CH:2]2[C:3]3[C:8](=[CH:7][C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:5][CH:4]=3)[CH2:9][CH2:10][CH2:11]2)[CH:21]=[N:20][CH:24]=1)=[O:26])([CH3:30])[CH3:29]
Reactant: CC(C)OC(=O)c1c[nH]cn1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cncn1C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reaction time: 1 h

Procedure:
To a suspension of trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (5.0 g, 0.016 mol) and isopropyl 4-imidazolecarboxylate, which can be prepared as described in Example 1 (1.72 g, 0.011 mol) in THF (100 mL) at 0° C. is added triphenylphosphine (4.20 g, 0.016 mol) and dimethyl azodicarboxylate (40% wt. in, toluene, 5.85 g, 0.016 mol). After 1 hour, the mixture is diluted with ethyl acetate and washed with water. The organic phase is dried with Na2SO4, filtered, and concentrated to give a residue, which is purified by silica gel chromatography (elution with hexanes-ethyl acetate mixtures) to give 3-(6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, MeOD) δ ppm 1.37 (t, J=6.8 Hz, 6 H), 1.88-1.97 (m, 2 H), 2.27-2.34 (m, 2 H), 2.96 (dd, J=17.4, 6.3 Hz, 1 H), 3.11 (dd, J=17.4, 6.6 Hz, 1 H), 5.22 (t, J=6.8 Hz, 1 H), 6.36 (t, J=6.2 Hz, 1 H), 7.06 (d, J=8.8 Hz, 1 H), 7.19 (dd, J=8.8, 2.5 Hz, 1 H), 7.29 (d, J=2.5 Hz, 1 H), 7.58 (s, 1 H), 7.76 (d, J=1.0 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27]>C(OCC)C>[Br-:20].[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]1([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:2]1[CH3:1])([OH:19])=[O:18]
Reactant: COCCOCCBr
Reactant: CC1=Nc2ccccc2C1(C)CCCCCC(=O)O
Solvent: CCOCC
Product: COCCOCC[N+]1=C(C)C(C)(CCCCCC(=O)O)c2ccccc21
Product: [Br-]
Temperature: 90 °C

Procedure:
To 6-(2,3-dimethyl-3H-indol-3-yl)hexanoic acid (100 mg) was added 1-bromo-2-(2-methoxyethoxy)ethane (1 ml) and the mixture heated to 90° C. overnight. On cooling diethyl ether (10 ml) was added and the material removed by filtration.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:8]=[C:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCCCCC.C(OC(=O)C)C>[Br:25][CH2:17][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([Cl:6])[CH:8]=1
Reactant: Cc1cc(Cl)cc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Clc1cc(CBr)c2ccccc2c1
Yield: 84 %

Procedure:
Carbon tetrachloride(30 ml) was added to 3-Chloro-1-methyl-naphthalene(2.55 g, 14.4 mmol) prepared in Preparation 36-1) and NBS (2.82 g, 15.8 mmol). A small quantity of benzoylperoxide was added as an initiator and the resulting mixture was heated under reflux for 3 hours. The reaction solution was cooled and filtered to remove the insoluble solid. The filtrate was concentrated and subjected to column chromatography(eluent: hexane/ethylacetate=95/5, v/v) to give 3.10 g(12.1 mmol, Yield 84%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([OH:12])=O)[CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1>>[NH:15]1[C:14]([NH:13][C:10]([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][N:7]=2)=[O:12])=[N:18][N:17]=[N:16]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccn1
Product: O=C(Nc1nnn[nH]1)c1cc([N+](=O)[O-])ccn1
Yield: 56.6 %

Procedure:
0.48 g of 4-nitro-2-pyridinecarboxylic acid, 0.48 g of N,N'-carbonyldiimidazole and 0.27 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from ethanol, whereby 0.38 g of N-(5-tetrazolyl)-4-nitro-2-pyridinecarboxamide is obtained.
Reaction SMILES: [C:1](OCC)(=[S:5])[C:2]([NH2:4])=O.Cl[CH2:10]C(=O)C.CCCCCC.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>C(O)C>[CH3:10][C:2]1[N:4]=[C:21]([C:20]([O:23][CH2:24][CH3:25])=[O:22])[S:5][CH:1]=1
Reactant: CC(=O)CCl
Reactant: CCOC(=S)C(N)=O
Reactant: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)c1nc(C)cs1
Yield: 22 %

Procedure:
Ethyl thiooxamate (3.0 g, 22 mmol) was dissolved in ethanol (30 mL) under argon. Chloroacetone (1.8 mL, 22 mmol) was added and the resultant solution was heated at 80° C. for 16 h. The reaction mixture was concentrated in vacuo, adsorbed onto silica gel, and purified by column chromatography on silica gel eluting with 97:3, then 95:5 hexane:ethyl acetate to afford ethyl 4-methyl-1,3-thiazole-2-carboxylate (850 mg, 22% yield) as an oil. 1H NMR (CDCl3, 300 MHz) 7.20 (s, 1H), 4.48 (q, J=7.1 Hz), 2.56 (s, 3H), 1.47 (s, 3H). MS (EI ionization) 171 (M+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[N:17]1[N:18]=[C:19]([SH:26])[N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[N:6]#[N:7].[N:17]1[N:18]=[C:19]([S:26][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)[N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12
Reactant: O=C(Nc1cn2nc(Cl)ccc2n1)C1CC1
Reactant: Sc1nnc2ccccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#N
Product: O=C(Nc1cn2nc(Sc3nnc4ccccn34)ccc2n1)C1CC1

Procedure:
6-Chloropyridazin-3-amine, N-(2-bromoacetyl)cyclopropanecarboxamide, and potassium hydrogenphosphate were mixed in DMA at 75° C. to provide N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide. N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide was reacted with [1,2,4]triazolo[4,3-a]pyridine-3-thiol and K2CO3 in DMA at 145° C. and 100 psi N2 to provide N-(6-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-yl)cyclo-propanecarboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]#[CH:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:16][O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C:14]#[CH:15]
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 3 h

Procedure:
The commercially available compound, 2-(R)-tert-butoxycarbonylaminopent-4-ynoic acid (0.321 g, 1.50 mmol) was dissolved in anhydrous DMF (5 mL). To the solution was added cesium carbonate (0.54 g, 1.65 mmol) in one portion. The mixture was stirred at room temperature for 45 min before methyl iodide (0.20 mL, 3.00 mmol) was added, and further stirred for three hours. The reaction was quenched with water (10 mL). The organics was extracted with dichloromethane (2×30 mL), washed with water (3×50 mL), and dried over anhydrous sodium sulfate. The solvent was completely removed under vacuum. The residue was further dried under high vacuum over night and used in the next reaction without further purification. The product 220 was obtained as a colorless viscous oil (0.326 g, 95% yield). 1H NMR (300 MHz, CDCl3): δ 1.48 (s, 9H), 2.08 (t, J=2.6 Hz, 1H), 2.75 (t, J=6.3 Hz, 2H), 3.78 (s, 3H), 4.46 (m, 1H), 5.32 (br s, 5H).
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:17][CH2:16][CH2:15][N:14]3[CH:18]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][N:22]=4)[N:20]=[C:13]3[C:12]=2[CH:29]=1)[CH3:7])(=O)=O.[N:30]1([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1>[CH:26]([N:25]1[C:21]([C:19]2[N:20]=[C:13]3[C:12]4[CH:29]=[C:8]([CH:6]([N:38]5[CH2:39][CH2:40][CH:35]([N:30]6[CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:36][CH2:37]5)[CH3:7])[CH:9]=[CH:10][C:11]=4[O:17][CH2:16][CH2:15][N:14]3[CH:18]=2)=[N:22][CH:23]=[N:24]1)([CH3:27])[CH3:28]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Solvent: C1COCCO1
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CCC(N2CCCC2)CC1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)ethyl methanesulfonate from Example 146 (246 mg, 0.590 mmol) and 4-(pyrrolidin-1-yl)piperidine (435 mg, 2.82 mmol) in 1,4-dioxane (4 mL) was stirred at 90° C. for 16 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 157. The enantiomers were separated by chiral HPLC (OD column, 30% EtOH (0.1% DEA) in n-hexane isocratic) to give: 52 mg of one enantiomer and 49 mg of the other (42% total yield)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[C:16](O)(=[O:20])[C:17]([CH3:19])=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClC(Cl)(Cl)C.C(C1CC(=CN(C)C)C=C(C(C)(C)C)C=1O)(C)(C)C>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)O
Reactant: O=C(O)c1ccc(OCCCCO)cc1
Agent: CN(C)C=C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)OCCCCOc1ccc(C(=O)O)cc1
Yield: 60 %

Procedure:
A solution of 282 g of 4-(4′-hydroxybutoxy)benzoic acid (1.34 mol), 325 ml of freshly distilled methacrylic acid (3.35 mol), 0.3 g of 2,6 di-tert-butyl-4-(dimethylaminomethylene)phenol (Ethanox® 703) and 23.7 g of p-toluenesulfonic acid in 1.1 l of 1,1,1-trichloroethane was refluxed for 10 hours on a water separator. The reaction mixture was cooled to 60° C.-70° C. and stirred into 2.51 of petroleum ether, and the precipitate was filtered off. After washing with petroleum ether, the precipitate was dried under reduced pressure at room temperature for 24 hours, giving 223.7 g of 4-(4′-methacryloxybutoxy)benzoic acid (yield 60%).