Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([S:27]([CH3:30])(=[O:29])=[O:28])[N:3]=1.[CH2:31]1[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[N:32]1[C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:9]([O:8][C:6]2[N:5]=[C:4]([S:27]([CH3:30])(=[O:29])=[O:28])[N:3]=[C:2]([N:38]3[CH2:37][CH2:36][C:35]4([CH2:31][N:32]([C:46]([O:48][CH2:49][C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)=[O:47])[C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34]4)[CH2:40][CH2:39]3)[CH:7]=2)[C:10]([F:12])([F:13])[F:11])=[C:15]([N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[CH:16]=1
Reactant: CCOC(=O)C1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(Cl)nc(S(C)(=O)=O)n2)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(S(C)(=O)=O)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 31.8 %

Procedure:
To a solution of 4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]-2-methylsulfonylpyrimidine (2.49 g, 5.17 mmol) in dioxane (100 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.8 g, 5.2 mmol), Cs2CO3 (5.06 g, 15.5 mmol), and the reaction mixture was heated to 100° C. for 1.5 h. The reaction mixture was cooled to RT, quenched with brine, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc:heptane) provided (S)-2-benzyl 3-ethyl 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid (1.3 g) in addition to (S)-2-benzyl 3-ethyl 8-(4-chloro-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH3:18][Si:19]([CH3:46])([CH3:45])[CH2:20][CH2:21][O:22][CH2:23][N:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([C:33]3[CH:34]=[N:35][N:36]([CH:38]4[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]4)[CH:37]=3)[C:27]=2[CH:26]=[CH:25]1>C1COCC1>[CH3:18][Si:19]([CH3:46])([CH3:45])[CH2:20][CH2:21][O:22][CH2:23][N:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([C:33]3[CH:34]=[N:35][N:36]([CH:38]4[CH2:43][CH2:42][C:41](=[CH:9][C:7]#[N:8])[CH2:40][CH2:39]4)[CH:37]=3)[C:27]=2[CH:26]=[CH:25]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4CCC(=O)CC4)c3)ncnc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4CCC(=CC#N)CC4)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.0 M potassium tert-butoxide in THF (1.90 mL) at 0° C. was added a solution of diethyl cyanomethylphosphonate (321 μL, 0.00198 mol) in THF (4 mL) dropwise. The reaction was held for 10 min, then it was added to a solution of 4-[4-(7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanone (743 mg, 0.00180 mol) in THF (5 mL) stirring at 0° C. under a nitrogen atmosphere. The reaction was stirred 1.5 h at rt. LCMS analysis showed clean conversion to the desired product. To the reaction mixture was then added water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic extract was washed with water, then sat'd NaCl, then dried over Na2SO4, and concentrated to dryness to yield 0.76 g of a white crystalline solid (TLC (EtOAc) Rf 0.33). The product was purified by automatic flash chromatography on silica gel. Used 40 g column; flow 40 mL/min; [A=hexane] [B=EtOAc]; A, 2 min; Gradient to B in 20 min. Rotary evaporation yielded 0.70 g of a white crystalline solid (89% yield). 1H NMR (CDCl3) δ 8.9 (s, 1H); 8.3 (s, 2H); 7.4 (d, 1H); 7.3 (s, 1H); 6.9 (d, 1H); 5.7 (s, 2H); 5.3 (s, 1H, olefin); 4.5 (m, 1H, NCH); 3.6 (m, 2H); 3.2 (m, 1H); 2.7 (m, 1H); 2.5 (m, 4H); 2.1 (m, 2H); 1.0 (m, 2H); −0.1 (s, 9H). MS (ES) 435 (M+1).
Reaction SMILES: [Na+].[O:2]=[C:3]1[CH:8]=[C:7]([C:9]([O-:11])=[O:10])[O:6][C:5]2[C:12]([CH2:20][CH2:21][CH3:22])=[C:13]3[C:18](=[CH:19][C:4]1=2)[CH2:17][CH2:16][CH2:15][CH2:14]3.[Na+].[OH:24]C1C2C(=O)C=C(C([O-])=O)OC=2C(CCC)=C2C=1CCCC2>>[OH:24][CH:14]1[C:13]2[C:18](=[CH:19][C:4]3[C:3](=[O:2])[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[O:6][C:5]=3[C:12]=2[CH2:20][CH2:21][CH3:22])[CH2:17][CH2:16][CH2:15]1
Reactant: CCCc1c2c(cc3c(=O)cc(C(=O)[O-])oc13)CCCC2
Reactant: CCCc1c2c(c(O)c3c(=O)cc(C(=O)[O-])oc13)CCCC2
Agent: [Na+]
Product: CCCc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2O

Procedure:
The title compounds were made using the techniques of Examples 1 and 2, but substituting 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho-[2,3-b]pyran-2-carboxylic acid sodium salt for the 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho-[2,3-b]pyran-2-carboxylic acid sodium salt. the product compounds were identified and characterised by gas liquid chromatographic nuclear magnetic resonnance spectrometry and other analytical techniques.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[CH3:32][N:33]1[C:37]([CH:38]=O)=[CH:36][N:35]=[CH:34]1>>[CH3:32][N:33]1[C:37]([CH2:38][NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=2[C:12]2[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:36][N:35]=[CH:34]1
Reactant: Cn1cncc1C=O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCc4cncn4C)ncn3)cccc2s1

Procedure:
N-(4-(6-(2-Amino-4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (prepared as described in WO04014871) was reacted with 1-methyl-1H-imidazole-5-carbaldehyde (Acros) under the conditions of Example 54 to give the title compound. MS (ESI, pos. ion) m/z: 540 (M+1). Mp: 263.0-265.2° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][C:10]#[N:11]>CC(C)=O.Cl.O>[CH:2]([CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][C:10]#[N:11])=[O:1]
Reactant: CC(C)(CCC#N)CC1OCCO1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(CC=O)CCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
50 g of 5-(dioxolan-2-yl)-4,4-dimethylvaleronitrile, prepared in D], are dissolved in 1.3 1 of acetone in the presence of 140 ml of concentrated hydrochloric acid and 700 ml of water. The mixture is stirred at room temperature for 5 hours, the acetone is concentrated under vacuum and the residue is taken up with ether, washed with water and then evaporated to dryness to give 35 g of 5-formyl-4,4-dimethylvaleronitrile.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.[CH:38]([C:41]1[S:42][C:43]([C:46]([N:48]2[CH2:53][C:52]3([CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[O:51][CH2:50][CH2:49]2)=[O:47])=[CH:44][N:45]=1)([CH3:40])[CH3:39].C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:56]2[CH2:55][CH2:54][C:52]3([O:51][CH2:50][CH2:49][N:48]([C:46]([C:43]4[S:42][C:41]([CH:38]([CH3:40])[CH3:39])=[N:45][CH:44]=4)=[O:47])[CH2:53]3)[CH2:58][CH2:57]2)=[CH:14][CH:13]=1)[C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: CC(C)c1ncc(C(=O)N2CCOC3(CCNCC3)C2)s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)s1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.575 g) in MeCN (3 mL) was added dropwise to a solution of (2-isopropylthiazol-5-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 114, step b) (0.229 g) and triethylamine (0.21 mL) in MeCN (7.3 mL) at RT under argon. The resulting mixture was stirred at 80° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM (25 mL), washed with brine (20 mL) and water (20 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-8% MeOH in DCM to give the subtitled compound as a yellow solid. Yield 0.395 g.
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23](=[O:30])[N:24]([CH2:26][CH2:27][O:28][NH2:29])[CH3:25])([CH3:21])([CH3:20])[CH3:19].Cl>CCO.C(OCC)C>[CH3:25][N:24]([CH2:26][CH2:27][O:28][N:29]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[NH:17][C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1)[C:23](=[O:30])[O:22][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(CCON)C(=O)OC(C)(C)C
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CN(CCON=C(c1ccccc1)c1cc2ccncc2[nH]1)C(=O)OC(C)(C)C
Reaction time: 15.5 h

Procedure:
A mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (200 mg, 90 mmol) and tert-butyl[2-(aminooxy)ethyl]methylcarbamate (Reference Example 14) (180 mg, 94 mmol) in EtOH (20 mL) was adjusted to pH 4-5 with HCl (1.2 mL of a 1 N HCl solution in diethyl ether, 1.2 mmol). The reaction mixture was heated to reflux. After 15.5 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (25 mL) and washed with saturated NaHCO3 (2×10 mL). The combined organic layers were washed with saturated NaCl (10 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 99:1 CH2Cl2/MeOH to 95:5 CH2Cl2/MeOH) gave tert-butyl methyl[2-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethyl]carbamate (geometry of the oxime double bond undefined).
Reaction SMILES: C1(C([NH:20][CH:21]2[C:40](=[O:41])[N:23]3[CH:24]([C:29]4[N:33]([CH2:34][C:35]5[O:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[N:31][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>CC(C)=O>[NH2:20][CH:21]1[C:40](=[O:41])[N:23]2[CH:24]([C:29]3[N:33]([CH2:34][C:35]4[O:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12.[CH3:53][C:43]1[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnnn1Cc1ccco1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnnn1Cc1ccco1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.422 g. (0.75 mmole) of 6-(triphenylmethylamino)-2,2-dimethyl-3(1-furfuryltetrazol-5-yl)penam in 1 ml of acetone at ambient temperature, is added 0.142 g. (0.75 mmole) of p-toluenesulfonic acid monohydrate. Stirring is continued for 30 minutes, and then the solvent is removed by evaporation in vacuo. This affords the title compound as its p-toluenesulfonate salt. IR (Nujol mull): 1780 cm-1 (B-lactam). NMR (DMSO-d6): 7.20 ppm (q,4H), 6.40 ppm (m,2H), 5.90 ppm (s,2H), 5.60 ppm (m,2H), 5.00 ppm (d,1H), 2.20 ppm (s,3H), 1.60 ppm (s,3H), 0.80 ppm (s,3H).
Reaction SMILES: CC(O)C.[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:14]([OH:17])[CH2:15]Cl)=[O:11])([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:14]1[O:17][CH2:15]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 4 °C
Reaction time: 7 h
Yield: 87 %

Procedure:
2-Propanol (2.4 ml) was added to (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (300 mg). After the mixture was cooled to 4° C., an aqueous solution (0.375 ml) of 4 mols/liter of sodium hydroxide and water (0.225 ml) were added thereto, and the mixture was stirred at 4° C. for 7 hours. After a 13.7% citric acid aqueous solution (695 mg) was added thereto, the mixture was extracted with tert-butylmethyl ether. The resulting organic layer was washed with water. It was identified by HPLC analysis that desired (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (230 mg) was obtained in a yield of 87%.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH:22]([CH3:24])[CH3:23])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH2:32](I)[CH2:33][CH3:34]>O>[CH:22]([N:3]1[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=[C:2]1[NH:1][CH2:32][CH2:33][CH3:34])([CH3:24])[CH3:23]
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C(C)C)c(=O)c23)c(C)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNc1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1C(C)C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of 2-amino-3-isopropyl-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (100 mg, 0.31 mmol) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 40 mg, 1.0 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of n-PrI (170 mg, 1.0 mmol) and N,N-dimethylformamide (2 ml) at 0° C. and stirred for 0.5 hour. After stirring at 50° C. for 3 hours, the mixture was cooled and diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (20:1) to give 68 mg (60%) of the title compound.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9](=[O:16])[CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH3:7]>ClCCl>[CH2:6]([O:8][C:9](=[O:16])[CH:10]([Cl:4])[C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[CH3:7]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1M solution of sulfuryl chloride in dichloromethane (25 mL, 25 mmol) was added to a solution of 4-methyl-3-oxopentanoic acid ethyl ester (3.95 g, 25 mmol) in dichloromethane (15 mL) cooled in a water bath. The solution was stirred at room temperature for 2 h and then the reaction mixture was washed with water (2×20 mL). Each of the aqueous layers was extracted with dichloromethane and the combined organic layers were dried (MgSO4), filtered and evaporated to give 2-chloro-4-methyl-3-oxopentanoic acid ethyl ester (5.0 g, 104% of the theoretical amount). This was used directly in the next step without purification.
Reaction SMILES: CS([O:5][CH:6]([CH:17]([CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)=O.[CH3:38][N:39]([CH:41](O)[CH2:42][CH2:43][CH3:44])[CH3:40].[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:18]([CH:17]([CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:6]([O:5][CH2:44][CH2:43][CH2:42][CH2:41][N:39]([CH3:40])[CH3:38])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCC(O)N(C)C
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OCCCCN(C)C
Temperature: 115 °C
Reaction time: 50 h
Yield: 12.7 %

Procedure:
A solution of the mesylate 61 (1.09 g, 2.01 mmol) in toluene (30 mL) was successively treated with N,N-dimethylaminobutanol (1.34 mL, 10.1 mmol) and NaH (442 mg as a 60% dispersion in oil, 11.1 mmol). Once gas evolution ceased the reaction mixture was brought to reflux (115° C. bath temp.) and stirred (50 h). The reaction mixture was then cooled (rt) and poured into cold water and then extracted with EtOAc. The combined organics were washed with water and brine, dried (Na2SO4), filtered, concentrated and purified via chromatography (100% EtOAc) to yield 4-(((6Z,16Z)-12-((Z)-dec-4-en-1-yl)docosa-6,16-dien-11-yl)oxy)-N,N-dimethylbutan-1-amine 62 (143 mg, 13%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.41-5.30 (m, 6H), 3.46-3.35 (m, 2H), 3.19-3.14 (m, 1H), 2.34 (t, 2H), 2.24 (s, 6H), 2.10-1.93 (m, 12H), 1.60-1.09 (m, 35H), 0.90 (t, 9H). Rf 0.54 (10% MeOH—CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:36][C:37]([N:39]1[CH2:48][CH2:47][C:42]2([O:46][CH2:45][CH2:44][O:43]2)[CH2:41][CH2:40]1)=[O:38]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:36][C:37]([N:39]3[CH2:40][CH2:41][C:42]4([O:46][CH2:45][CH2:44][O:43]4)[CH2:47][CH2:48]3)=[O:38])[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC(=O)N2CCC3(CC2)OCCO3)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
To N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (4.65 g, 11.5 mmol) and cesium carbonate (10.08 g, 30.94 mmol) was added N,N-Dimethylformamide (40 mL) and stirred at room temperature for 5 minutes. To this was added 2-Chloro-1-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)ethan-1-one (5.34 g, 20.2 mmol) in N,N-Dimethylformamide (4.5 mL) and stirred at room temperature for 3 and a half hours. LC/MS (method 31) shows reaction complete. The reaction was then filtered and the filtrate was concentrated under reduced pressure to give a red oil. This was then dissolved in 30 mL dichloromethane and purified by ISCO using a silica column and eluting with 0-100% Ethyl acetate in heptane in 5 minutes followed by 0-15% Methanol in dichloromethane to give 5.16 g (8.78 mmol) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)-2-oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow foamy solid. LC/MS (method 39) [M+H]+=589.2, RT=1.91 min.
Reaction SMILES: [F:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][CH2:8][CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[C:25]3[N:24]=[C:23]([C:26]([F:29])([F:28])[F:27])[S:22][C:21]=3[NH:20][C:19]3[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=3[N:17]=2)[CH2:11]1.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][CH2:2][C:3]([N:15]1[CH2:14][CH2:13][N:12]([C:16]2[C:25]3[N:24]=[C:23]([C:26]([F:28])([F:29])[F:27])[S:22][C:21]=3[NH:20][C:19]3[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=3[N:17]=2)[CH2:11][C@@H:10]1[CH2:9][CH2:8][O:7][CH3:6])=[O:4]
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Reactant: O=C(Cl)CF
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1C(=O)CF
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Add a solution of fluoroacetyl chloride (0.133 g, 1.38 mmol) in anhydrous dichloromethane (1-2 mL) dropwise to a 0° C. solution of (S)-10-[3-(2-Methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.283 g, 0.688 mmol) and diisopropylethylamine (0.240 mL, 1.38 mmol) in anhydrous dichloromethane, and stir at 0° C. for 3 hours. Concentrate the reaction under reduced pressure to afford an oil. Purify the oil by flash chromatography, eluting with a gradient of a solution of 2% 2M ammonia in methanol, in dichloromethane (0-100% in dichloromethane over 30 minutes, then 100% for 28 minutes) to give the title compound: 0.18 g (56%). Mass spectrum (APCI+, m/e): 472 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-:30].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:28])=[O:30])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cc1
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of (4-(7-chloro-1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (134.5 mg) obtained in Example 116 and potassium carbonate (94 mg) in DMSO (2 mL) was added 30% aqueous hydrogen peroxide (139 μL) at room temperature. The reaction mixture was stirred overnight, and poured into water. The precipitated crystals were collected by filtration, and purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), to the obtained fraction was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified to give the title compound (105 mg).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4](=[O:15])[NH:3]1.CC(C)([O-])C.[K+].Br[CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(O)(C)(C)C>[CH3:14][O:13][C:11]([CH:10]1[CH2:9][CH2:8][CH2:7][N:6]2[C:2](=[O:1])[N:3]([CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[C:4](=[O:15])[N:5]12)=[O:12]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COC(=O)C1CCCn2c(=O)[nH]c(=O)n21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C1CCCn2c(=O)n(CC(=O)OCc3ccccc3)c(=O)n21
Reaction time: 4 h
Yield: 52.2 %

Procedure:
1.50 g (0.007 mol) of methyl hexahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate were dissolved in 40 ml of dry tert.butanol. A solution of 0.87 g (0.008 mol) of potassium tert.butoxide in 50 ml of dry tert.butanol was added and the mixture was stirred under reflux and under a nitrogen atmosphere for 4 hours. 1.61 g (0.007 mol) of benzyl bromoacetate were added and the heating was continued for a further 4 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel using chloroform for the elution to give 1.32 g (52%) of benzyl 5-methoxycarbonyl-2,3,5,6,7,8-hexahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-2-acetate of melting point 103°-106° C. (from dichloromethane/hexane).