Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Al](C)C.C([O:22][C:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:32]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[O:33])[N:26]=1)=O)C.O>O1CCOCC1>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[NH:1][C:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:32]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[O:33])[N:26]=1)=[O:22]
Reactant: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-n2ccccc2=O)cc1F)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (259 mg; CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) at r.t. in dioxane (4 ml) under an argon atmosphere was added trimethylaluminium (0.63 ml; 2 M solution in heptane)-->foaming. The mixture was stirred at r.t. for 2 h. A solution of 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (100 mg) in dioxane (4 ml) was then added. The mixture was heated to 100° C. over night. The mixture was cooled to r.t. and H2O (0.8 ml) was added (-->bubbling). After 15 min stirring, MgSO4 was added and stirring was continued for another 15 min. The mixture was then filtered and the cake was washed with dichloromethane. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide as light yellow solid. 474.1 ([M+H]+)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: OCCc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(CCO)cc2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (2.94 g) and 1-fluoro-4-nitrobenzene (3.0 g) in dimethylformamide (21 mL) was added potassium carbonate (4.41 g) and the solution was stirred at 120° C. for 4 hours. After cooling to room temperature, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the title compound having the following physical data.
Reaction SMILES: Br.Br[C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:6][NH:5][C:4]=1[NH2:14].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:22]=[C:23]=[S:24])=[O:21].N1C=CC=CC=1.CS(C)=O>O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:3]2[S:24][C:23]([NH:22][C:20]([C:16]3[O:15][CH:19]=[CH:18][CH:17]=3)=[O:21])=[N:14][C:4]=2[NH:5][N:6]=1
Reactant: O=C(N=C=S)c1ccco1
Reactant: Nc1[nH]nc(-c2ccccn2)c1Br
Agent: Br
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc2[nH]nc(-c3ccccn3)c2s1)c1ccco1
Reaction time: 0.08 h

Procedure:
A mixture of 4-bromo-5-pyridin-2-yl-2H-pyrazol-3-ylamine hydrobromide salt (193 mg, 0.60 mmol), furan-2-carbonyl isothiocyanate (0.07 mL), pyridine (0.1 mL), and DMSO (2 mL) was placed in a Smith process vial. The reaction was run in a Personal Chemistry SmithCreator microwave at 160° C. for five minutes. The reaction mixture was then added to an excess of water and the resulting precipitate was filtered. Purification by preparative HPLC afforded 10 mg of furan-2-carboxylic acid (3-pyridin-2-yl-1H-pyrazolo[3,4-d]thiazol-5-yl)-amide as a white solid. 1H-NMR (d6-DMSO) δ: 8.60 (dd, 1H), 7.92 (m, 2H), 7.80 (d, 1H), 7.46 (d, 1H), 7.26 (m, 2H), 6.60 (dd, 1H); HPLC/MS m/z: 312 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]3[O:39][CH:38]([C:40]([OH:42])=[O:41])[CH2:37][C:36]=3[CH:43]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O.COCCOC.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>[ClH:1].[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:32]2[CH:33]=[CH:34][C:35]3[O:39][CH:38]([C:40]([OH:42])=[O:41])[CH2:37][C:36]=3[CH:43]=2)[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[N:5]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(OC(F)(F)F)cc2)n1
Reactant: CC1(C)OB(c2ccc3c(c2)CC(C(=O)O)O3)OC1(C)C
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(OC(F)(F)F)cc2)cc(-c2ccc3c(c2)CC(C(=O)O)O3)n1
Product: Cl
Temperature: 60 °C
Yield: 31.8 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2(4-trifluoromethoxyphenyl)-ethyl]amine [475 mg, 1.36 mmol, Intermediate (13)], 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-carboxylic acid (266 mg, 0.91 mmol), Cs2CO3 (1.19 g, 3.6 mmol) and tetrakis(triphenylphosphine)palladium (146 mg, 0.13 mmol) in water (2 mL) and ethylene glycol dimethyl ether (8 mL) is degassed with bubbling nitrogen for 5 minutes and heated at 60° C. for 23 hours. The reaction mixture is cooled, diluted with water (200 mL) and brine (50 mL), and acidified with 1N hydrochloric acid to pH 5. The mixture is extracted three times with EtOAc (150 mL) and the extracts are concentrated in vacuo. The residue is subjected to flash column chromatography on silica (5 g) eluting with 0 to 20% MeOH in ethyl acetate. The product is dissolved in ether and treated with 1 M hydrogen chloride in ether to afford 5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-2,3-dihydro-benzofuran-2-carboxylic acid hydrochloride (148 mg, Example 88) as a solid. MS: 476 (M+H); LCMS: RT=2.78 minutes, MS: 474 (M−H). IC50=3.1 nM
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[NH:43]1[CH:46]([C@@H:47]2[CH2:51][C@H:50]([SH:52])[CH2:49][N:48]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])[CH2:45][C:44]1=[O:66]>>[NH:43]1[CH:46]([C@@H:47]2[CH2:51][C@H:50]([S:52][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[CH2:49][N:48]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])[CH2:45][C:44]1=[O:66]
Reactant: O=C1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)N1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 70.9 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (153 mg, 0.27 mmol) and (2S,4S)-2-(2-azetidinon-4-yl)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer A (90 mg, 0.26 mmol, compound of Reference Example 4) to obtain p-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-(2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer A (128 mg, yield: 70.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[CH:8]=O.[C:10]1([C:16]2[O:17][C:18]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]2[C:19]=3[CH2:20][C:21](=[O:28])[NH:22]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1.Cl>CC(O)C.O>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:20]1\[C:21](=[O:28])[NH:22][C:23]2[CH:24]=[CH:25][C:26]3[N:27]=[C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[O:17][C:18]=3[C:19]\1=2
Reactant: O=C1Cc2c(ccc3nc(-c4ccccc4)oc23)N1
Reactant: COc1cc[nH]c1C=O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: C1CCNCC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3nc(-c4ccccc4)oc3c21

Procedure:
3-Methoxypyrrole-2-carboxaldehyde (13 mg, 0.105 mmol)(Bellamy, supra) and 2-phenyl-6,8-dihydro-oxazolo[5,4-e]-indol-7-one (17 mg, 0.068 mmol)(Starting Material 4) were suspended in a solution of 10% piperidine (Aldrich) in 2-propanol (1 mL). The mixture was heated at reflux for 2 h. The mixture was cooled, poured into water, and the aqueous mixture was made acidic with concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the crude product was purified by reverse phase HPLC using acetonitrile—water as solvent. (Yield 10 mg, 41%).
Reaction SMILES: [Br-:1].C([O:5][C:6]1[C:15]2[N+:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Br:16])(=O)C.[O:17]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOCC>C(O)(C)C>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([NH3+:28])=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1.[Br-:16].[Br:16][C:7]1[CH:8]=[CH:9][N+:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[OH:5].[Br-:1]
Reactant: CC(=O)Oc1c(Br)cc[n+]2ccccc12
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CC(C)O
Product: Oc1c(Br)cc[n+]2ccccc12
Product: [NH3+]c1ccc(Oc2ccccc2)cc1

Procedure:
To a solution of 1-acetoxy-2-bromoquinolizinium bromide (12.0 g., 0.035 mole) in isopropanol (250 ml.) was added p-phenoxyaniline (15.0 g., 0.08 mole). The stirred mixture was boiled under reflux for 3.5 hours. The reaction mixture was treated with ether and scratched, and the precipitate was removed by filtration and dried at 63°. The mustard-yellow product weighed 11.0 g. (65%). Recrystallization from isopropanol/ether provided gold crystals melting at 123°-125°.
Reaction SMILES: [N:1]1([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH2:28])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:1]1([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH:28][C:33]([NH:34][C:35]5[N:36]([C:44]6[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=6)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=5)=[O:32])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCCC4)n3c2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCCC5)n4c3)c3ccccc32)cc1
Yield: 10 %

Procedure:
A solution of Intermediate 67b (173 mg, 0.458 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 186 mg, 0.458 mmol) in 1,4-dioxane (3 mL) and DIPEA (122 μL, 0.700 mmol) was stirred at 95° C. for 3.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM. Further purification by FCC, using 0-10% MeOH in DCM, gave impure product. This was further purified by HPLC (C18 X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give impure product. Further purified by HPLC (XBridge column, 35-98% MeCN in H2O, 0.1% NH4OH) to give an off-white powder after freeze-drying (50 mg). This material was further purified by MDAP (Method 7) to give the title compound as a white solid (28 mg, 10%). LCMS (Method 5): Rt 4.77 min, m/z 633.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.64-1.71 (4H, m), 1.74-1.97 (6H, m), 1.99-2.18 (2H, m), 2.36 (3H, s), 3.38-3.43 (4H, m, under water signal), 4.77-4.85 (1H, m), 5.47 (1H, t, J 4.3), 6.32 (1H, s), 7.07-7.14 (2H, m), 7.25-7.40 (8H, m), 7.55-7.59 (2H, m), 8.06 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[H-].[Na+].CN(C)C=O.[CH3:17][O:18][C:19](=[O:22])[CH2:20]Br>O>[CH3:17][O:18][C:19](=[O:22])[CH2:20][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(Br)ccc1O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-bromo-2-methylphenol (1.0 g, 5.35 mmol), sodium hydride (0.26 g, 6.42 mmol, 60% mineral oil), N,N-dimethylformamide (10 mL), and methyl-2-bromoacetate (0.56 mL, 5.88 mmol) is stirred at room temperature 18 hr. The mixture is diluted with water (50 mL) and the product extracted to ethyl acetate (3×50 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered, concentrated and purified via silica chromatography eluting with 8:2 hexanes:ethyl acetate to afford title compound as a colorless oil, 1.03 g, 74%. MS M+ 259. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:17]=O)[CH:14]=[N:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:19].[NH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>>[ClH:19].[F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:17]=[N:20][OH:21])[CH:14]=[N:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: O=Cc1cncc(C#Cc2ccc(F)c(F)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: ON=Cc1cncc(C#Cc2ccc(F)c(F)c2)c1
Yield: 35.4 %

Procedure:
Prepare in a similar manner as described in EXAMPLE 6 using 5-(3,4-difluorophenylethynyl)-pyridine-3-carbaldehyde (0.28 g, 1.15 mmol), (prepared essentially as described in EXAMPLE 101), hydroxylamine hydrochloride (0.64 g, 9.21 mmol) and potassium carbonate (0.80 g, 5.76 mmol) to give the title compound (0.120 g, 35%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16](C(OCC)=O)[CH:15]([CH3:24])[CH2:14]2)=[CH:4][CH:3]=1.[OH-].[K+]>CC(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH3:24])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCN(CCCCC(c2ccc(F)cc2)c2cccnc2)CC1C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC1CN(CCCCC(c2ccc(F)cc2)c2cccnc2)CCN1
Reaction time: 96 h
Yield: 67.6 %

Procedure:
A mixture of 12 parts of ethyl 4-(5-(4-fluorophenyl)-5-(3-pyridinyl)pentyl]-2-methyl-1-piperazinecarboxylate, 16 parts of potassium hydroxide and 128 parts of 2-propanol was stirred for 4 days at reflux temperature. After cooling, the reaction mixture was evaporated. Water was added to the residue and the mixture was evaporated till all traces of 2-propanol were removed (this was repeated twice). The residue was taken up in water and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 6.7 parts (67.6%) of 1-(5-(4-fluorophenyl)-5-(3-pyridinyl)pentyl]-3-methylpiperazine as a residue (int. 39).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:22])=[N:10]2.S(=O)(=O)(O)O.[N+:28]([O-])([OH:30])=[O:29].[OH-].[Na+]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:28]([O-:30])=[O:29])=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:19])([F:21])[F:20])[C@H:14]1[CH2:13][S:12][C:11]([NH2:22])=[N:10]2
Reactant: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4aS,5S,7aS)-7a-(2,3-Difluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (1.42 g) was dissolved in TFA (6 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 1 mL) was added, followed by fuming nitric acid (0.30 mL) dropwise over 20 mins. After stirring at 0° C. for 1 h, the reaction mixture was poured onto ice (50 g) and basified to pH 12 with 2 N NaOH (aq.). After allowing the ice to melt, the mixture was extracted with EtOAc (3×75 mL), and the combined organic portions dried over MgSO4 and evaporated to afford the title compound (1.91 g, purity approx. 80%) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.88 (dd, J=13.8, 3.9 Hz, 1H), 3.11 (dd, J=13.6, 2.8 Hz, 1H), 3.37 (dt, J=7.4, 3.5 Hz, 1H), 3.93 (d, J=7.8 Hz, 1H), 4.53-4.83 (m, 4H), 8.09 (ddd, J=9.0, 6.3, 2.9 Hz, 1H), 8.27 (dt, J=5.2, 2.6 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1.CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O[Si](C)(C)C(C)(C)C

Procedure:
3,5-Dichloro-4-(3'-isopropyl-4'-hydroxyphenoxy)-nitrobenzene (10.2 g), 6.75 g. of t-butyldimethylsilyl chloride, 4.06 g of imidazole, and 2 mg of N ,N-dimethylaminopyridine in 10 ml dimethylformamide are stirred 18 hours at room temperature. The solution is poured into ether and extracted six times with water. The ether is dried, filtered and stripped to afford 3,5-dichloro-4-(3'-isopropyl-4'-t-butyldimethylsiloxyphenoxy)-nitrobenzene. NMR (CDCl3): δ0.2 (6H, s), 1.1 (9H,s), 1.2 (6H,d), 3.3 (1H,m), 6.5 (1H,d of d), 6.7 (1H,d), 8.3 (2H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:15]([Mg]Br)[CH2:16][CH3:17].BrCCC.[Mg]>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([NH2:14])[CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)cc(C2(C#N)CCC2)c1
Reactant: CCC[Mg]Br
Agent: [Mg]
Solvent: CCCBr
Solvent: CCOCC
Product: CCCC(N)C1(c2cc(C)cc(Cl)c2)CCC1
Product: Cl
Temperature: 50 °C

Procedure:
A solution of 1-(3-chloro-5-methylphenyl)-1-cyclobutanecarbonitrile (8.0 g) in ether (40 ml) was added to a solution of propyl magnesium bromide [prepared by the reaction of 1-bromopropane (6.7 g) and magnesium (1.3 g)] in ether (80 ml) and the mixture heated under reflux for two and a half hours. Two thirds of the ether was evaporated off and then, after cooling, a solution of sodium borohydride (3.5 g) in ethanol (150 ml) added. The mixture was maintained at 50° C. for one hour and water (50 ml) and then 5N hydrochloric acid (50 ml) added. The ether layer was separated, dried and evaporated to yield a solid which was recrystallised from propan-2-ol to give 1-[1-(3-chloro-5-methylphenyl)cyclobutyl]butylamine hydrochloride (m.p. 145°-146° C.).
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[Cl:7][C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[NH:10][C:9]=1[C:15]([NH:17][C@H:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([C:32]([CH:35]=[O:36])=[CH:33][N:34]=2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][C@H:19]1[O:37][CH3:38])=[O:16]>O.CC(C)=O>[Cl:7][C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[NH:10][C:9]=1[C:15]([NH:17][C@H:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([C:35]([OH:1])=[O:36])=[CH:33][N:34]=2)[CH2:20][C@H:19]1[O:37][CH3:38])=[O:16]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 133 mg (0.84 mmol) KMnO4 in 5 ml water was added to a solution of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-formylisonicotinate (Example 154) in 20 ml acetone, and the mixture was stirred at room temperature for 4 h. After quenching with aqueous NaHSO3, the mixture was acidified to about pH=4 with 1N HCl and extracted twice with EtOAc. The EtOAc extracts were washed with brine, dried (MgSO4) and concentrated to give a solid that was triturated with MeOH to give 175 mg of product. MS (ES) MH+: 499 for C21H24Cl2N4O6; NMR: 1.25 (t, 3H), 1.5-1.8, (m, 3H), 2.1 (s, 3H), 3.1 (m, 3H), 3.3 (s, 3H), 3.5 (m, 1H), 4.2 (m, 2H), 4.4 (m, 1H), 4.9 (m, 1H), 6.9 (s, 1H), 7.1 (d, 1H), 8.6 (s, 1H), 12.1 (s, 1H), 13.3 (s, 1H).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])C1.[CH3:12]I.[C:14](#N)[CH3:15]>>[CH3:12][C:14]1([CH3:15])[C:1](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:10]
Reactant: CC#N
Reactant: CI
Reactant: O=C1CC(=O)c2ccccc21
Product: CC1(C)C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Preparations of compounds listed in the above Table I are given below for illustrative purposes. ##STR76## 20 g (0.137 moles) of indan-1,3-dione was added to 200 ml of acetonitrile. 26 ml (0.41 moles) of methyl iodide and 8 g of a KF-celite (1:1) mixture were then added to this mixture and the resulting red mixture stirred for 18 hours at 60° C. under a nitrogen atmosphere. After cooling, the precipitate was filtered off and washed with acetonitrile. The filtrate was then evaporated to dryness and the residue chromatographically purified using a silica column with hexane/ether (6:4) as the eluent. 10.5 g of 2,2-dimethyl-indan-1,3-dione was obtained with a melting point of 107° C. ##STR77##
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:21])[N:8]([C:11]3[C:18]([F:19])=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=3[F:20])[CH:9]=[CH:10][C:5]=2[NH:4][N:3]=1.[Br:22]Br>C(O)(=O)C>[BrH:22].[NH2:1][C:2]1[C:6]2[C:7](=[O:21])[N:8]([C:11]3[C:12]([F:20])=[CH:13][C:14]([C:15]#[N:16])=[CH:17][C:18]=3[F:19])[CH:9]=[C:10]([Br:22])[C:5]=2[NH:4][N:3]=1
Reactant: BrBr
Reactant: N#Cc1cc(F)c(-n2ccc3[nH]nc(N)c3c2=O)c(F)c1
Solvent: CC(=O)O
Product: Br
Product: N#Cc1cc(F)c(-n2cc(Br)c3[nH]nc(N)c3c2=O)c(F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(3-amino-4-oxo-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-3,5-difluorobenzonitrile obtained in Step B (0.60 g) and acetic acid (40 mL) was slowly added bromine (0.21 mL) at 80° C., and the reaction mixture was stirred at 100° C. for 1 hr. The solvent was evaporated under reduced pressure, and the residue was recrystallized from acetic acid to give the title compound (0.81 g).