Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH2:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:21]=[CH:22]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccncc2N)CC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(n2cnc3cnccc32)CC1
Yield: 73.5 %

Procedure:
To a solution of 4-(3-amino-pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (10.0 g, 34.20 mmol, 1.0 equiv) and triethyl orthoformate (10.14 g, 68.40 mmol, 2.0 equiv) in anhydrous toluene (70 mL) was added toluene-4-sulfonic acid (0.59 g, 3.42 mmol, 0.1 equiv) and the reaction mixture heated to reflux for 16 h. The solvent was removed by evaporation under reduced pressure and the residue triturated with diethyl ether. The preciptate was filtered off, washed with diethyl ether and dried under reduced pressure to yield 7.6 g (73%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.43 (s, 9H), 1.92-2.04 (m, 4H), 2.95 (br s, 2H), 4.13 (br s, 2H), 4.64 (t, J=3.8 Hz, 1H), 7.75 (d, J=5.5 Hz, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.55 (s, 1H), 8.95 (s, 1H). MS (ISP): 303.2 [M+H]1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([C:18]([NH:20][C:21]4[S:22][CH:23]=[CH:24][N:25]=4)=[O:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:26]1[CH2:29][CH2:28][CH2:27]1.[F-].[Cs+].CC([O-])(C)C.[K+]>CN(C=O)C.O>[N:26]1([C:2]2[CH:7]=[C:6]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[C:11]([C:18]([NH:20][C:21]5[S:22][CH:23]=[CH:24][N:25]=5)=[O:19])[CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Nc1nccs1)c1cccc2ccc(-c3ccnc(Cl)c3)nc12
Reactant: C1CNC1
Agent: CC(C)(C)[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)c1cccc2ccc(-c3ccnc(N4CCC4)c3)nc12
Temperature: 150 °C
Yield: 23.5 %

Procedure:
A mixture of 2-(2-chloropyridin-4-yl)-N-(thiazol-2-yl)quinoline-8-carboxamide (200 mg, 0.55 mmol), azetidine (314 mg, 5.5 mmol), CsF (84 mg, 0.55 mmol) and t-BuOK (185 mg, 1.65 mmol) in DMF (4 mL) under N2 was microwave heated (150° C.×12 min). The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (10% methanol in CH2Cl2) to obtain of 2-(2-(azetidin-1-yl)pyridin-4-yl)-N-(thiazol-2-yl)quinoline-8-carboxamide as a solid (50 mg, 23% yield). MS (ESI) calcd for C21H17N5OS (m/z): 387.12. found: 388 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH3:10])=[CH2:9])=[CH:6][C:5]([NH:11][C:12](=[O:14])[CH3:13])=[C:4]([O:15][CH3:16])[CH:3]=1.[CH2:17](I)I.[Zn](CC)CC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]2([CH3:17])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:11][C:12](=[O:14])[CH3:13])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: C=C(C)c1cc(NC(C)=O)c(OC)cc1Cl
Reactant: ICI
Agent: CC[Zn]CC
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c(C2(C)CC2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a solution of N-(4-chloro-2-methoxy-5-(prop-1-en-2-yl)phenyl)acetamide (1.0 g, 4.17 mmol) in toluene (20 mL) at 0° C., CH2I2 (5.6 g, 20.86 mmol) and Et2Zn (41.7 mL, 41.7 mmol, 1.0 M in hexane) was added. The mixture was kept at 0° C. for 30 min, and then stirred at RT for 16 h. The reaction mixture was quenched with saturated NH4Cl solution and stirred for 15 min. The mixture was concentrated in vacuo to remove toluene and the resulting mixture was extracted with dichloromethane. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated to afford the desired product (820 mg, 77% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=[O:22])[C:16]=2Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=[O:22])[C:16]=2[C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=C(Br)C1=O
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=C(c2ccncc2)C1=O
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
To a solution of 5-(4-(benzyloxy)phenyl)-4-bromo-2,2-dimethylfuran-3(2H)-one (1.0 g, 2.67 mmol) in toluene (10 mL) were added pyridin-4-ylboronic acid (362 mg, 2.94 mmol), Cs2CO3 (4.3 g, 13.3 mmol) followed by water (5 mL) under an inert atmosphere. The reaction mixture was stirred for 15 minutes and then Pd(dppf)Cl2 (430 mg, 0.0005 mmol) was added. This mixture was refluxed for 16 h and then filtered through a pad of Celite®. The filtrate was extracted with EtOAc (2×40 mL) and the combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 40% EtOAc in hexanes to afford 5-(4-(benzyloxy)phenyl)-2,2-dimethyl-4-(pyridin-4-yl)furan-3(2H)-one (620 mg, 62%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].CN(C)CCN(C)C.C([Li])CCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[C:10]([O:9][C:8]([NH:7][C:2]1[C:3]([B:28]([OH:33])[OH:29])=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncccc1B(O)O
Temperature: -6 °C

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl N-(2-pyridyl)carbamate (15.71 g, 80.9 mmol) and N,N,N′,N′-tetramethylethylenediamine (TMEDA, 25.3 g, 218 mmol) in THF (400 mL) was cooled to −78° C. n-Butyllithium (81 mL of a 2.5 M solution in hexanes) was added dropwise over a period of 20 minutes. The solution was stirred for ten minutes, and then the addition funnel was rinsed with additional THF (20 mL). The solution was warmed to −6° C., stirred for two hours, and cooled again to −78° C. Triisopropyl borate (57.7 g, 307 mmol) was added over a period of ten minutes. The resulting solution was warmed to 0° C. and then poured into saturated aqueous ammonium chloride (500 mL). A yellow solid formed and was stirred with diethyl ether (300 mL), isolated by filtration, washed with diethyl ether and water, and air-dried overnight to provide 2-tert-butoxycarbonylamino-3-pyridylboronic acid as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:30])[CH3:29])[C:23]=1[S:31]([NH2:34])(=[O:33])=[O:32]>>[CH3:29][N:28]([CH3:30])[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([NH:21][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3)[N:3]=2)[C:23]=1[S:31]([NH2:34])(=[O:33])=[O:32]
Reactant: CN(C)c1cccc(N)c1S(N)(=O)=O
Reactant: COc1cc(Nc2nccc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2nccc(Nc3cccc(N(C)C)c3S(N)(=O)=O)n2)cc(OC)c1OC

Procedure:
2-(Dimethyl-amino)-6-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide is prepared as described in Example 1 step C by using 4-chloro-pyrimidin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine (example 1 step A) and 2-amino-6-dimethylamino-benzenesulfonamide.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6](O)(=[O:9])[CH2:7]C.C[C:12]1[CH:17]=[C:16]([C:18](C)(C)C)[C:15]([OH:22])=C(C(C)(C)C)[CH:13]=1>>[CH2:6]([O:9][C:15](=[O:22])[CH:16]([CH3:18])[CH:17]=[C:12]=[CH2:13])[CH3:7]
Reactant: CCC(=O)O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: C=C=CC(C)C(=O)OCC
Temperature: 150 °C

Procedure:
The autoclave is closed and the reaction mass is heated to 150° C. over a period of 50 minutes. The reaction mass is then maintained at a temperature of between 135°-160° C and at a pressure of 20 up to 60 psig for a period of 3 hours. At the end of this 3-hour period, the autoclave is cooled to room temperature and then opened. 12.6 g of sodium bicarbonate is then added to the reaction mass in order to neutralize the propionic acid. 30 g of Primol (see note 1) and 0.1 g of Ionol (see note 2) are added and the resulting reaction product is fractionally distilled at atmospheric pressure to a pot temperature of 129° C. A mixture of ethanol and ethyl propionate is distilled over. Vacuum is then applied to the distillation column and the resultant product, ethyl-2-methyl-3,4-pentadienoate is distilled at a vapor temperature of 65°-69° C at a pressure of 24-33 mm Hg as fractions 5-10 of the following fractions:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].[Br:17][C:18]1[N:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[N:8]=3)[CH2:10][CH2:11]2)=[CH:22][N:23]=1
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Reactant: Oc1ccc(Br)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3ccc(Br)nc3)CC2)n1
Yield: 28.9 %

Procedure:
Alternative preparation: Step 1: 2-Bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (220 mg, 29%) was prepared as a white solid from {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Steps 1-3, 348 mg, 2.0 mmol), 6-bromo-3-pyridinol (348 mg, 2.0 mmol) and Ph3P (629 mg, 2.4 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.51 mL, 2.6 mmol) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H), 7.37 (d, 1H, J=8.8 Hz), 7.08 (d, 1H, J=8.8 Hz), 4.26-4.16 (m, 2H), 3.85 (d, 2H, J=6.2 Hz), 3.14-3.04 (m, 2H), 2.95-2.76 (m, 1H), 2.11-1.96 (m, 1H), 1.98-1.88 (m, 2H), 1.52-1.36 (m, 2H), 1.28 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 381/383 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[C:14]([NH:16][C:17]4[CH:25]=[CH:24][C:20]5[CH:21]=N[O:23][C:19]=5[CH:18]=4)[N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2N3N=C(N)N=C3C=CC=2)C=CC=CC=1.BrC1C=CC(C=O)=C([F:51])C=1.C1(NC2N=C3C=CC=C(C4C=CC=CC=4)N3N=2)C=CC=CC=1>>[F:51][C:21]1[CH:18]=[C:17]([NH:16][C:14]2[N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:12]3[N:13]=2)[CH:25]=[CH:24][C:20]=1[CH:19]=[O:23]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: c1ccc(-c2cccc3nc(Nc4ccc5cnoc5c4)nn23)cc1
Agent: Nc1nc2cccc(-c3ccccc3)n2n1
Agent: c1ccc(Nc2nc3cccc(-c4ccccc4)n3n2)cc1
Product: O=Cc1ccc(Nc2nc3cccc(-c4ccccc4)n3n2)cc1F

Procedure:
N-(5-Phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzo[d]isoxazol-6-amine. 2-Fluoro-4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzaldehyde was prepared from 5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 4-bromo-2-fluoro-benzaldehyde following the procedure described for the synthesis of N,5-diphenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>ClCCl>[CH3:21][S:18]([O:10][CH:3]([CH2:2][CH3:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:20])=[O:19]
Reactant: CCCCCCC(O)CC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(CC)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
20 g (138.6 mmol) of 3-nonanol and 15.43 g of triethylamine are dissolved in 150 ml of dichloromethane and admixed dropwise with 17.47 g (152.5 mmol) of mesyl chloride. The mixture is stirred at room temperature for 4 hours. The organic phase is extracted twice with water and dried over sodium sulphate and the solvent is removed under reduced pressure. This gives 30.7 g (95%) of a yellow liquid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH:41]1([CH2:47][C@H:48]([NH:81][C:82]([O:84][CH2:85][C:86]2[CH:91]=[CH:90][C:89]([N+:92]([O-:94])=[O:93])=[CH:88][CH:87]=2)=[O:83])[C@@H:49]([OH:80])[CH2:50][C:51]([NH:53][C@H:54]2[CH2:58][CH2:57][N:56]([C:59]([C@@H:61]3[CH2:65][C@H:64]([SH:66])[CH2:63][N:62]3[C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([N+:77]([O-:79])=[O:78])=[CH:73][CH:72]=3)=[O:68])=[O:60])[CH2:55]2)=[O:52])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:66][C@@H:64]3[CH2:63][N:62]([C:67]([O:69][CH2:70][C:71]4[CH:72]=[CH:73][C:74]([N+:77]([O-:79])=[O:78])=[CH:75][CH:76]=4)=[O:68])[C@H:61]([C:59]([N:56]4[CH2:57][CH2:58][C@H:54]([NH:53][C:51](=[O:52])[CH2:50][C@H:49]([OH:80])[C@@H:48]([NH:81][C:82]([O:84][CH2:85][C:86]5[CH:91]=[CH:90][C:89]([N+:92]([O-:94])=[O:93])=[CH:88][CH:87]=5)=[O:83])[CH2:47][CH:41]5[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]5)[CH2:55]4)=[O:60])[CH2:65]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)C[C@H](O)[C@H](CC5CCCCC5)NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 72.6 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-diphenylphosphoryloxy-1-carbapen-2-em-3-carboxylate (1.53 g) and (2S,4S)-2-[(3S)-3-[(3S,4S)-5-cyclohexyl-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)aminopentanoylamino]pyrrolidin-1-ylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.00 g), reaction and purification were carried out in a similar manner to that described in Example 1-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[(3S)-3-[(3S,4S)-5-cyclohexyl-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)aminopentanoylamino]pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (2.10 g) was obtained as an amorphous substance.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]([S:19]([OH:22])(=[O:21])=[O:20])([F:18])([F:17])[F:16]>>[S:19]([O:22][S:19]([C:15]([F:18])([F:17])[F:16])(=[O:21])=[O:20])([C:15]([F:18])([F:17])[F:16])(=[O:21])=[O:20]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reaction time: 18 h

Procedure:
Triflic anhydride was prepared as follows: 170 g. (100 ml.) CF3SO3H ("Fluorochemic acid" 3M Company) and 135 g. P2O5 were mixed carefully, shaken well, and stored 18 hours protected from moisture. The product was distilled from the resulting solid mass using a flame; the fraction boiling 80°-90° C. was collected. Re-distillation of this fraction yielded 119.45 . (74%) of triflic anhydride boiling 82°-84° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:22]([OH:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]([CH:26]=[O:27])[C:18]=2[CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]2[C:22]([OH:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]([CH2:26][OH:27])[C:18]=2[CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1c(C)c(C=O)c(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1c(C)c(CO)c(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
To a solution of 7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoic acid (1.8 g) in tetrahydrofuran (30 ml) was added sodium borohydride (176 mg) at 0° C. and the mixture was stirred at room temperature for 2 hours. Acetone was added and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added and the organic layer was separated. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crystals. They were recrystallized from acetonitrile to obtain 7-(4-fluorophenyl)-7-(6-hydroxy-3-hydroxymethyl-2,4,5-trimethylphenyl)heptanoic acid (740 mg) (Compound 32). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: C[NH:2][S:3]([CH2:6]Cl)(=[O:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.C(N(CC)CC)C>CCOCC>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:6][S:3](=[O:5])(=[O:4])[NH:2][C:16]2=[O:17])=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CNS(=O)(=O)CCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1NS(=O)(=O)CN1c1ccc(Cl)cc1
Yield: 31.3 %

Procedure:
A 50-ml flask was charged with 5.0 grams (0.035 mol) of N-methyl chloromethane sulfonyl chloride (from Example 1) and 5.3 grams (0.035 mol) of p-chlorophenylisocyanate. Then 3 ml of triethylamine were added. There was an exothermic reaction, and the mixture turned solid. After standing for 3/4 hour at 25° C., ether was added to form a slurry. This slurry was filtered to give a white solid which was reslurried in ether, filtered and dried to give 2.7 grams of 4-p-chlorophenyl-1,2,4-thiadiazolidine-1,1,3-trione having a melting point of 155°-157° C. Analysis for C9H9ClN2O3S: S, 12.3%; Cl, 13.6%. Found, S, 12.4%; Cl, 13.7%. The infrared spectra had strong absorption at 1720, 1485, 1435, 1370, 1340, 1280, 1255, and 1145 cm-1. The NMR spectra in 6D-dimethylsulfoxide had major peaks at 7.7 (4H), 5.6 (2H), and 3.3 (3H) ppm, and minor peaks at 4.0 and 2.8 ppm.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:38])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]3[C:34]4[C:29](=[C:30]([C:35](=[O:37])[NH2:36])[CH:31]=[CH:32][CH:33]=4)[N:28]=[CH:27][N:26]=3)[CH:18]=2)[CH:10]=1)C)(C)(C)C.Cl>O1CCOCC1>[CH3:6][NH:7][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][NH:24][C:25]1[C:34]2[C:29](=[C:30]([C:35]([NH2:36])=[O:37])[CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][N:26]=1)=[O:38]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1
Reaction time: 8 h

Procedure:
59 mg (0.11 mmol) (3-{3-[(8-Carbamoyl-quinazolin-4-ylamino)-methyl]-phenylcarbamoyl}-phenyl)-methyl-carbamic acid tert-butyl ester were dissolved in 3 ml dioxane and 560 μl 4 N HCl in dioxane were added. The mixture was stirred overnight, filtered and washed with dioxane.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[CH:3]=1.[NH2:19]C1C2C(Cl)=CN(COC(O)CCO)C=2N=CN=1>>[NH2:19][C:9]1[C:10]2[C:2]([Br:1])=[CH:3][N:4]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1ncnc2c1c(Cl)cn2COC(O)CCO
Reactant: OCCC(O)OCn1cc(Br)c2c(Cl)ncnc21
Product: Nc1ncnc2c1c(Br)cn2COC(O)CCO

Procedure:
Compound 22b was prepared from 5-bromo4-chloro-7-[(1,3-dihydroxypropoxy)methyl]pyrrolo[2,3-d]pyrimidine by the method described for 22a to yield 0.27 g (20%). mp=170°-172° C. 1H NMR (DMSO-d6): δ3.15-3.50 (m, 5); 4.59 (t, 2, exchanges with D2O, OH); 5.57 (s, 2, C-1'), 6.80 (bs, 2, exchanges with D2O, NH2); 7.53 (s, 1, C-6); 8.11 (s, 1, C-2). Anal. Calcd. for C10H13N4O3Br. (C,H,N).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[C:22]([C:24]2[N:25]=[N:26][N:27]([CH2:29][CH:30]3[CH2:34][O:33]C(C)(C)[O:31]3)[CH:28]=2)[CH:21]=[CH:20][C:19]=1[CH3:37])=[O:17].Cl.CCOC(C)=O.O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[C:22]([C:24]2[N:25]=[N:26][N:27]([CH2:29][CH:30]([OH:31])[CH2:34][OH:33])[CH:28]=2)[CH:21]=[CH:20][C:19]=1[CH3:37])=[O:17]
Reactant: Cc1ccc(-c2cn(CC3COC(C)(C)O3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cn(CC(O)CO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of compound 123 (1.05 g, 2.02 mmol) in THF (10 mL) was added HCl (10 mL, aq., 10, 1N) and the mixture was stirred for 16 h at RT. The reaction mixture was poured into a mixture of EtOAc/water/NaHCO3. The organic phase was washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 10:90 as the eluent to afford the title compound as white solid.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:40]=[CH:39][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]5)=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:42][C:2]([F:1])([F:41])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:13][CH2:14][CH:15]([C:18]4[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:28][CH2:27]5)=[CH:39][CH:40]=4)[CH2:16][CH2:17]3)[CH2:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
10% Palladium on carbon (0.859 g, 0.81 mmol) was added to tert-butyl 4-[3-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]propyl]piperazine-1-carboxylate (2.38 g, 4.04 mmol) and ammonium formate (2.55 g, 40.36 mmol) in ethanol (100 mL). The resulting mixture was stirred at 78° C., with further portions of ammonium formate being added every 5 hours until the reaction was complete. The reaction mixture was cooled to room temperature and the catalyst was removed by filtration. The filtrate was evaporated to dryness, the residue was re-dissolved in DCM (100 mL) and the solution was washed with water (50 mL) and brine (50 mL). The solvents were evaporated to give tert-butyl 4-[3-[4-(1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]phenoxy]propyl]piperazine-1-carboxylate (2.090 g, 88%) as a solid.