Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[C:38]/[CH:39]=[CH:40]/[CH2:41]O)=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:41]/[CH:40]=[CH:39]/[C:38]#[C:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:32][CH:33]=1)=[O:9]
Reactant: OC/C=C/C#Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/C#Cc2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
30 mg (0.089 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 21 mg (0.089 mM) of (E)-5-[4-(1-imidazolylmethyl)phenyl)-pent-2-en-4-yn-1-ol, 22 mg (0.107 mM) of dicyclohexylcarbodiimide and 12 mg (0.098 mM) of 4-N,N-dimethylaminopyridine were dissolved in 3 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 49 mg (87%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=3)=[C:12]([C:26]3[CH:31]=[CH:30][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=3)[S:11][C:10]=2[CH:37]=1)(=[O:4])=[O:3].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.[I-].[K+].C([Cl:48])(=O)C>CO.CN(C)C=O>[ClH:48].[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:17][CH:16]=3)=[C:12]([C:26]3[CH:31]=[CH:30][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=3)[S:11][C:10]=2[CH:37]=1)(=[O:4])=[O:3]
Reactant: C1CCNC1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCBr)cc2)cc1
Reactant: CC(=O)Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.19 g. portion of the product of Example 30 above, 20 ml. of anhydrous dimethylformamide and 3.4 g. of freshly distilled pyrrolidine were added to a flask at 25°, and then 100 mg. of powdered potassium iodide was added and the mixture was stirred at ambient temperature for 1 hour. The mixture was then evaporated under vacuum, 25 ml. of saturated aqueous sodium bicarbonate was added, and the mixture was extracted twice with 25 ml. portions of ethyl acetate. The extract was washed five times with 20 ml. portions of aqueous sodium chloride, and was dried over magnesium sulfate and evaporated to a brown oil. The oil was dissolved in 25 ml. of hydrochloric acid in methanol, which had been prepared by addition of 10 ml. of acetyl chloride to 100 ml. of methanol under nitrogen at 0°. The mixture was then evaporated to dryness under vacuum, and the resulting foam was crystallized from denatured ethanol to provide 1.07 g. of crystals, m.p. 206°-207°.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1>>[CH3:11][C:9]1[S:10][C:6]2[C:5]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=[C:2]([NH:18][C:19]3[S:20][CH:21]=[C:22]([CH3:24])[N:23]=3)[C:7]=2[N:8]=1
Reactant: Cc1csc(N)n1
Reactant: Cc1nc2c(Cl)ncc(-c3cccnc3)c2s1
Product: Cc1csc(Nc2ncc(-c3cccnc3)c3sc(C)nc23)n1

Procedure:
The title compound, MS: m/e=340.1 (M+H+), was prepared in accordance with the general method of example 2, step 2 from 4-chloro-2-methyl-7-pyridin-3-yl-thiazolo[4,5-c]pyridine and 2-amino-4-methylthiazole.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4](Cl)[N:3]=1.[CH3:12][SH:13].C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4]([S:13][CH3:12])[N:3]=1
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Reactant: CS
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(N)c(C=O)nc1Cl
Reaction time: 0.5 h

Procedure:
In 3 ml of dimethylformamide there was dissolved 2-amino-5,6-dichloro-3-formylpyrazine (384 mg; 0.002 M), and the solution was cooled in an ice bath. Through the solution there was then bubbled methanethiol gas for 2 minutes. Triethylamine was added, and more methanethiol gas was bubbled through the solution for 3 minutes. The reaction mixture was stirred in the ice bath for 30 minutes and then at room temperature for 30 minutes. The solvent and methanethiol were then removed under nitrogen atmosphere, and the residue was treated with water. The product precipitated, was filtered, and washed with water (333 mg). Elemental Analysis for C6H6N3OSCl.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([NH2:14])=[N:8][NH:9]2.CC(N(CC1C=CC(CN2C3C(=C(OC)C=CC=3)C(NS(C3SC(Cl)=CC=3)(=O)=O)=N2)=CC=1)C(=O)[O-])(C)C.Cl[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[C:56]([O:62][CH3:63])[CH:55]=1>CS(C)=O.O>[CH3:63][O:62][C:56]1[CH:55]=[C:54]([CH2:53][N:9]2[C:10]3[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=3)[C:7]([NH2:14])=[N:8]2)[CH:59]=[CH:58][C:57]=1[O:60][CH3:61]
Reactant: COc1cccc2[nH]nc(N)c12
Reactant: COc1ccc(CCl)cc1OC
Agent: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(CN(C(=O)[O-])C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(N)c3c(OC)cccc32)cc1OC
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Powdered KOH (0.494 g, 8.80 mmol) was dissolved in DMSO (20 mL) under nitrogen and 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (0.653 g, 4 mmol) was added. The mixture was stirred for 15 min to give a deep red solution. 4-(Chloromethyl)-1,2-bis(methyloxy)benzene (0.896 g, 4.80 mmol) was added in one portion and the mixture was stirred for 2 h. The mixture was added to water (150 mL) and extracted with dichloromethane (3×50 mL). The dried (Na2SO4) extract was evaporated and the residue was triturated with diethyl ether (3×3 mL) to give the title compound (1.05 g, 84%) as an orange solid. LCMS (System B) RT=2.22 min, ES+ve m/z 314 (M+H)+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[C:18]1[CH:22]=[C:21]([S:23][CH3:24])[N:20]([CH3:25])[N:19]=1.O>C(Cl)(Cl)(Cl)Cl>[Cl:4][C:22]1[C:18]([C:8]2[C:7]([Cl:6])=[CH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:10][C:9]=2[Cl:17])=[N:19][N:20]([CH3:25])[C:21]=1[S:23][CH3:24]
Reactant: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1c(Cl)c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 0.3 g quantity of sulfuryl chloride was added to 1.2 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-5-methylsulfenylpyrazole (compound 1) in 5 ml of anhydrous carbon tetrachloride at room temperature, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into cold water, and the resulting mixture was extracted with methylene chloride. The organic layer was washed with 10% aqueous sodium hydrogen carbonate solution and with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was then purified by column chromatography on silica gel (eluent: ether/hexane=1/5), giving 1.0 g of the desired compound in the form of white crystals (yield 83.3%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:17][C:18]1([Cl:25])[CH2:20][C:19]1([CH3:24])[C:21](O)=[O:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:17][C:18]1([Cl:25])[CH2:20][C:19]1([C:21]([N:12]1[CH2:11][CH2:10][N:9]([C:4]2[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13]1)=[O:22])[CH3:24]
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: CC1(C(=O)O)CC1(Cl)Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)CC1(Cl)Cl
Yield: 56 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2,2-dichloro-1-methylcyclopropanecarboxylic acid (100 mg, 0.59 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-[(2,2-dichloro-1-methylcyclopropyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 56% yield (127 mg) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:13]1[S:17][N:16]=[C:15](Cl)[N:14]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[H-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:13]1[S:17][N:16]=[C:15]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[N:14]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CN(CCCNC(=O)OC(C)(C)C)c1nc(Cl)ns1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CCCNC(=O)OC(C)(C)C)c1nc(-n2ccnc2)ns1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
{3-[(3-Chloro-[1,2,4]thiadiazol-5-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester (6.50 g, 21.2 mmol) was combined with imidazole (7.20 g, 105 mmol) and dissolved in DMSO (100 mL). Next, the sodium hydride (833 mg of a 60% dispersion on mineral oil, 57.8 mmol) was added the reaction mixture was stirred at 60° C. overnight. After this period, brine was added to the reaction mixture and it was transferred to a separatory funnel. The product was extracted with copious DCM and the organic layer was dried over anhydrous Na2SO4. The crude material was purified by flash silica chromatography (Hex to 1:4 Hex/EtOAc) to yield 6.78 g (94%) of {3-[(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester as a clear oil. [M+H]+ 339.10.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[C:8]([NH:10][C:11]2[CH:16]=[N:15][C:14]([C@@H:17]3[CH2:21][O:20]C(C)(C)[O:18]3)=[CH:13][N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[C:8]([NH:10][C:11]2[CH:16]=[N:15][C:14]([C@@H:17]([OH:18])[CH2:21][OH:20])=[CH:13][N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](c2cnc(NC(=O)C(CC3CCCC3)n3ncc(Oc4c(F)cccc4F)cc3=O)cn2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1cnc([C@@H](O)CO)cn1)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[5-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-propionamide (685 mg, 1.26 mmol) in methanol (12.6 mL, 0.1 M) and methylene chloride (5 mL) was treated with para-toluenesulfonic acid (36 mg, 0.18 mmol). The reaction stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous sodium bicarbonate solution (150 mL), water (150 mL), and a saturated aqueous sodium chloride solution (150 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[5-((R)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-propionamide as an off-white solid (0.50 g, 81%); ES+-HRMS m/e calcd for C24H25N5O5F2 [M+H+] 502.1897 found 502.1894. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.21 (m, 1H), 1.27-1.85 (m, 8H), 1.91-2.08 (m, 1H), 2.22-2.41 (m, 1H), 3.50-3.62 (m, 1H), 3.62-3.73 (m, 1H), 4.62 (q, J=5.1 Hz, 1H), 4.72 (t, J=5.7 Hz, 1H), 5.52-5.64 (m, 2H), 6.07 (d, J=2.5 Hz, 1H), 7.33-7.56 (m, 3H), 8.31 (d, J=2.5 Hz, 1H), 8.45 (s, 1H), 9.13 (s, 1H), 11.25 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([OH:14])[C:11]([O:15][CH3:16])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8].[N+:17]([O-])([OH:19])=[O:18]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[C:13]([N+:17]([O-:19])=[O:18])=[C:12]([OH:14])[C:11]([O:15][CH3:16])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COc1cc2sc(C(=O)O)c(Cl)c2cc1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2sc(C(=O)O)c(Cl)c2c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Chloro-5-hydroxy-6-methoxy-benzo[b]thiophene-2-carboxylic acid (0.28 g) was dissolved in ethyl acetate and a solution of nitric acid in dichloromethane (2M, 0.75 ml) was gradually added at 20° C. into. The solution was stirred at room temperature for 10 min and then it was poured into ice-cold water and extracted with ethyl acetate and evaporated to dryness.
Reaction SMILES: C(O)(=[O:3])C.C([O-])(=O)C.[Na+].[Br:10][C:11]1[CH:12]=[C:13]([CH2:29][C:30]([OH:32])=[O:31])[CH:14]=[C:15]([Br:28])[C:16]=1[O:17][C:18]1[N:19]=[N:20][C:21](Cl)=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:12]=[C:13]([CH2:29][C:30]([OH:32])=[O:31])[CH:14]=[C:15]([Br:28])[C:16]=1[O:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:3])[NH:20][N:19]=1
Reactant: CC(C)c1cc(Oc2c(Br)cc(CC(=O)O)cc2Br)nnc1Cl
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Oc2c(Br)cc(CC(=O)O)cc2Br)n[nH]c1=O
Temperature: 120 °C
Yield: 73 %

Procedure:
A solution of 2-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-ethanol (12) (111.4 g, 247 mmol) in acetonitrile (223 mL), methylene chloride (343 mL) and sodium phosphate buffer (343 mL of a 0.67 M solution, pH=6.7) was treated with 2,2,6,6-tetramethyl-1-piperidinyloxy free group (2.35 g, 14.83 mmol) at room temperature. A solution of sodium chlorite (44.71 g, 395.5 mmol) in water (135 mL) and a solution of sodium hypochlorite (28 mL, 24.5 mmol) in water (50 mL) were then added simultaneously to the reaction mixture over 45 min. The temperature of the reaction mixture rose to 40° C. during the addition and a cold water bath was used to prevent the temperature from going any higher. The brown reaction mixture was stirred for 30 min. While cooling with cold water, a solution of sodium bisulfite (28.42 g, 297 mmol) in water (86 mL) was added dropwise to the reaction mixture over 5 min. The yellow solution was diluted with methylene chloride (223 mL) and extracted. The layers were separated and the organic layer was extracted with water (2×200 mL), dried with sodium sulfate, filtered and concentrated under vacuum to afford [3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-acetic acid (13). Glacial acetic acid (549 mL) and sodium acetate (40.56 g, 494 mmol) were added to [3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-acetic acid (13). The reaction mixture was heated to 120° C. for 24 h. At this time, the reaction mixture was cooled to room temperature, diluted with toluene (200 mL) and concentrated under vacuum two times. The resulting residue was diluted with tetrahydrofuran (223 mL) and isopropyl acetate (892 mL) and was washed with water (3×150 mL). The organic layer was separated and concentrated under vacuum to about 600 mL. Isopropyl acetate (180 mL) was added and the mixture was concentrated under vacuum to about 450 mL. Heptane (300 mL) was added in portions over 10 min. The mixture was stirred under reflux for 15 min and then was cooled to room temperature. The resulting solid was filtered, washed with 50% isopropyl acetate in heptane (200 mL), and dried under high vacuum overnight to afford [3,5-dibromo-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-acetic acid (14) (80.4 g, 73%) as a white solid; LRMS for C15H14Br2N2O4 (M+H) m/z=446. Molecular Weight=446.0978; Exact Mass=443.9320
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=1.CS(C)=O.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH:3]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=1)=[O:2]
Reactant: COC(OC)c1ccncc1OCc1cccc(C(=O)O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1ccncc1OCc1cccc(C(=O)O)n1
Temperature: 45 °C
Reaction time: 3.5 h

Procedure:
Into an 8-mL sealed tube, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylic acid (150 mg, 0.49 mmol, 1.00 equiv) in dichloromethane (4 mL) and trifluoroacetic acid (2 mL). The resulting solution was stirred for 3.5 h at 45° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (10% MeCN up to 35% in 4 min, up to 100% in 1 min, down to 10% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 49 mg (38%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-2-carboxylic acid as a light yellow solid. LC-MS-PH-GBT-ZL-HS-19-0 (ES, m/z): 259 [M+1]+ H-NMR-PH-GBT-ZL-HS-19-0 (300 MHz, DMSO, ppm): 10.52 (s, 1H), 8.92 (s, 1H), 8.52 (d, J=4.8 Hz, 1H), 8.09 (m, 2H), 7.95 (m, 1H), 7.76 (d, J=4.8 Hz, 1H), 5.61 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2].O.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:29](OC)(OC)[O:30]C>CO>[CH3:18][O:3][C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][CH:9]=1)([O:30][CH3:29])[CH3:2]
Reactant: COC(OC)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Solvent: CO
Solvent: O
Product: COC(C)(OC)c1cnc(NC(=O)C(C)(C)C)cn1
Yield: 72 %

Procedure:
A suspension of N-(5-acetyl-pyrazin-2-yl)-2,2-dimethyl-propionamide (prepared as in Example 28, 2.00 g, 9.038 mmol) in trimethyl orthoformate (13.5 mL) and methanol (36 mL) was treated with p-toluenesulfonic acid monohydrate (174.5 mg, 0.904 mmol). The resulting reaction mixture was heated under reflux for 2.5 h and then concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (100 mL) and a saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/4 ethyl acetate/hexanes) afforded N-[5-(1,1-dimethoxy-ethyl)-pyrazin-2-yl]-2,2-dimethyl-propionamide as a white solid (1.74 g, 72%): mp 108–109° C.; EI-HRMS m/e calcd for C13H21N3O3 (M+) 267.1583, found 267.1486.
Reaction SMILES: [F:1][CH2:2][C:3](=[CH2:17])[CH2:4][N:5]([CH2:11][CH:12](OC)[O:13]C)[C:6](=[O:10])[O:7][CH2:8][CH3:9].C(O)=O.[Cl-].[Na+]>O>[F:1][CH2:2][C:3](=[CH2:17])[CH2:4][N:5]([CH2:11][CH:12]=[O:13])[C:6](=[O:10])[O:7][CH2:8][CH3:9]
Reactant: C=C(CF)CN(CC(OC)OC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: C=C(CF)CN(CC=O)C(=O)OCC

Procedure:
25 g (0.1 mol) of ethyl N-(2-fluoromethylallyl)-N-(2,2-dimethoxyethyl)carbamate are heated under reflux for two hours with 5 g of formic acid in 100 ml of water. The mixture is saturated with sodium chloride and extracted with methylene chloride, and the organic phases are washed with sodium hydrogen carbonate solution until neutral. They are dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: COC(C1CC2C(=CC=CC=2)C1)=O.[F:14][C:15]([F:33])([F:32])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:30][CH:29]3[NH:31][CH:25]([CH2:26][CH2:27][CH2:28]3)[CH2:24]2)=[CH:19][CH:18]=1.[CH3:34][O:35][C:36]([CH:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][C:44]=2[S:47](Cl)(=[O:49])=[O:48])[CH2:39]1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:34][O:35][C:36]([CH:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][C:44]=2[S:47]([N:31]2[CH:29]3[CH2:28][CH2:27][CH2:26][CH:25]2[CH2:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]([F:14])([F:32])[F:33])=[CH:18][CH:19]=2)[CH2:30]3)(=[O:49])=[O:48])[CH2:39]1)=[O:37]
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: FC(F)(F)Oc1ccc(N2CC3CCCC(C2)N3)cc1
Agent: COC(=O)C1Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Temperature: 50 °C

Procedure:
4-|3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo|3.3.1|nonane-9-sulfonyl|-indan-2-carboxylic acid methyl ester: A mixture of 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane (60 mg, 0.21 mmol), 4-chlorosulfonyl-indan-2(R,S)-carboxylic acid methyl ester (120 mg, 0.44 mmol), potassium carbonate (200 mg, 1.4 mmol), and acetonitrile (3 mL) were heated at 50° C. for 2 h. The mixture was filtered through Celite, concentrated, and purified by silica gel chromatography (9:1→4:1; hexanes:ethyl acetate) to give 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid methyl ester: MS (ESI): 525.5 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>CCO>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:33][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)[CH:3]=1)=[O:15]
Reactant: NC1CCNCC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(NC3CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 1.5 h
Yield: 35 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (60 mg, 0.16 mmol) and 4-piperidinamine (2 mL) in EtOH (3 mL). The vessel was sealed and the reaction mixture was irradiated (microwave) at 125° C. for 5 hr and then at 160° C. for 90 min. The mixture was evaporated under vacuum and the resulting residue was partitioned between EtOAc and water. Organics were washed with water (2×) and brine, dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOAc/ether (1:1) and allowed to stand at room temperature overnight. The solids that had precipitated were triturated, filtered, and dried to afford the title compound as a pale yellow solid 25 mg (35%). LCMS E-S (M+H)=438.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (t, J=4.67 Hz, 1H) 7.98 (s, 1H) 7.12 (s, 1H) 5.89 (s, 1H) 4.98 (dt, J=13.33, 6.60 Hz, 1H) 4.30-4.41 (m, 4H) 3.01 (t, J=11.62 Hz, 2H) 2.85 (br. s., 1H) 2.20 (s, 3H) 2.12 (s, 3H) 1.80 (d, J=10.36 Hz, 2H) 1.44 (s, 3H) 1.43 (s, 3H) 1.18-1.30 (m, 3H) 0.79-0.91 (m, 1H)