Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([CH:12](Br)[C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2].C(#N)C.[N+]1([O-:27])C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[O:27])[C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2]
Reactant: [O-][n+]1ccccc1
Reactant: CCOC(=O)Nc1nc(C(Br)C(=O)OC)ns1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Nc1nc(C(=O)C(=O)OC)ns1
Yield: 93.6 %

Procedure:
Into a 1 L round bottom flask equipped with mechanical stirring and reflux condenser was charged methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)-bromoacetate (50.0 g, 0.154 mol, 1.0 eq.) followed by acetonitrile (500 mL). To the clear light yellow solution was charged pyridine N-oxide (37.0 g, 0.385 mol, 2.5 eq) and the reaction mixture was heated to reflux and maintained there for three hours until reaction completion was determined by proton NMR analysis. The solution was cooled and the acetonitrile was removed by rotary evaporation to give a thin yellow oil. The oil was dissolved in dichloromethane (500 mL) and the organic was washed once with brine (1×200 mL). The brine solution was extracted several times with dichloromethane (5×100 mL) and the organic layers were combined and dried with sodium sulfate, filtered and the solvent evaporated to give a clear slightly yellow oil which solidified upon standing at room temperature. The solid was dried under high vacuum to give 37.36 grams of the title compound. 1H NMR (CDCl3) δ 1.40 (t, 3H); 4.06 (s, 3H); 4.46 (q, 2H).
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][CH2:4][CH2:5]CC.[C:9]1([CH2:15][O:16][CH2:17][C:18]([O:20]C)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([CH2:15][O:16][CH2:17][C:18](=[O:20])[CH2:1][C:2](=[O:8])[CH2:3][CH2:4][CH3:5])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)COCc1ccccc1
Reactant: CCCCCC(C)=O
Product: CCCC(=O)CC(=O)COCc1ccccc1

Procedure:
From 2-heptanone and methyl phenylmethoxyacetate according to the method of Intermediate 16.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[N:19]=2)[CH:15]=[CH:14][S:13]3)[CH:7]=[CH:8][CH:9]=1)#[N:3].C(N(CC)CC)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>ClCCl>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([S:45]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[N:16]5[C:12]([S:13][CH:14]=[CH:15]5)=[N:11][C:10]=4[C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([C:2]#[N:3])[CH:5]=4)[CH:23]=[CH:22][N:21]=3)[CH2:26]2)(=[O:47])=[O:46])=[CH:41][CH:40]=1
Reactant: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
The 4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine hydrochloride (˜5.79 mmol) in dichloromethane (DCM) (50 mL) was cooled to 0° C. and treated with triethylamine (4.0 mL, 28.9 mmol), then 4-chlorophenylsulfonyl chloride (1.34 g, 6.37 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, diluted with dichloromethane (100 mL), washed with water (50 mL×3), dried over sodium sulfate and concentrated in vacuo to provide 3.22 g (97%) of the title compound as a yellow solid. M.p.=144-146° C.; 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.65 (br. s, 1H), 8.17 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.94 (dd, J=0.8 and 7.6 Hz, 1H), 7.82-7.85 (m, 1H), 7.77-7.75 (m, 2H), 7.67-7.64 (m, 3H), 7.44 (d, J=4.4 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 6.37 (d, J=4.8 Hz, 1H), 3.91 (bs, 1H), 3.72 (d, J=10.8 Hz, 1H), 3.48 (d, J=10.8 Hz, 1H), 2.48-2.45 (m, 1H), 2.32 (t, J=10 Hz, 1H), 1.89-1.82 (m, 2H), 1.60-1.56 (m, 1H), 1.41-1.36 (m, 1H). LCMS: 576 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Ca+2].[I:14](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[NH2:1][C:2]1[C:7]([I:14])=[N:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
23.2 g (180.5 mM) of 5-amino-2-chloropyridine are mixed in 70 ml of dichloro-methane (DCM) and 180 ml of methanol, and 21.6 g (216 mM) of calcium carbonate and 75.3 g (226 mM) of benzyltrimethylammonium dichloroiodate are added. The reaction mixture is stirred at room temperature for 16 hours, and then filtered to remove the mineral salts. The filtrate is diluted with water and extracted with DCM. The organic phase obtained is washed with sodium chloride solution, and then with saturated sodium thiosulfate solution, dried over magnesium sulfate and concentrated under reduced pressure. An oil is obtained, which is purified by chromatography on silica gel, eluting with a cyclohexane/ethyl acetate mixture (80/20 and then 70/30; v/v). 13.9 g of the expected product are thus obtained in the form of an orange-colored solid (yield=30%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C(C(O)=O)[CH:11]=[N:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].CN(C)C=O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:1]([C:2]([Cl:4])=[O:3])[CH:11]=[N:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ncc(C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.4 %

Procedure:
Oxalyl chloride (0.07 ml, 0.800 mmol) was added to a stirred solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (WO 2008074820; 86 mg, 0.40 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at 0° under nitrogen and the mixture was allowed to warm to room temperature with stirring overnight. The solvent was evaporated in vacuo to give a yellow gum (123 mg) which was used in the subsequent reaction (D53) without further purification
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([CH:16]=O)=[N:14][N:13]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:10]3=[N:11][CH:12]=2)[CH:2]=1.[F:24][C:25]1[CH:26]=[C:27]([C:31]2[C:32]([NH2:38])=[C:33]([NH2:37])[CH:34]=[N:35][CH:36]=2)[CH:28]=[CH:29][CH:30]=1.[S]>C(O)CCC>[F:24][C:25]1[CH:26]=[C:27]([C:31]2[C:32]3[N:38]=[C:16]([C:15]4[C:9]5[C:10](=[N:11][CH:12]=[C:7]([C:3]6[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=6)[CH:8]=5)[N:13]([CH:18]5[CH2:23][CH2:22][CH2:21][CH2:20][O:19]5)[N:14]=4)[NH:37][C:33]=3[CH:34]=[N:35][CH:36]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ncc(-c3cccnc3)cc12
Reactant: Nc1cncc(-c2cccc(F)c2)c1N
Agent: [S]
Solvent: CCCCO
Product: Fc1cccc(-c2cncc3[nH]c(-c4nn(C5CCCCO5)c5ncc(-c6cccnc6)cc45)nc23)c1
Temperature: 25 °C

Procedure:
A solution of 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (CXXXI) (65 mg, 0.21 mmol), 5-(3-fluorophenyl)pyridine-3,4-diamine (LXXV) (45 mg, 0.22 mmol) and sulfur (7 mg, 0.22 mmol) in n-butanol (10 mL) was heated at reflux overnight. The solution was cooled to room temperature, filtered and the solvent was evaporated under reduced pressure to give crude 3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (CXXXII). CXXXII was dissolved in dry DCM (5 mL) before adding triethylsilane (84 μL, 0.52 mmol) and TFA (2.5 mL). The reaction was stirred at room temperature for 2 h under argon. The solvent was evaporated under reduced pressure; the residue was taken up water (10 mL), and basified with 5N NH4OH. The precipitates were filtered, washed by cold water and dried under vacuum at room temperature. The crude product was suspended in DCM (10 mL), sonicated briefly and then heated to boiling for 5 min. The solution was cooled to room temperature and the solids were filtered, washed with DCM and dried under vacuum at room temperature to produce 3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (3) as a yellow solid (53 mg, 0.13 mmol, 62% yield). 1H NMR (DMSO-d6) δ ppm 7.25-7.34 (m, 1H), 7.54-7.65 (m, 2H), 8.11-8.21 (m, 1H), 8.23-8.30 (m, 1H), 8.37-8.50 (m, 1H), 8.63-8.70 (m, 1H), 8.70-8.80 (m, 1H), 9.02-9.09 (m, 2H), 9.09-9.15 (m, 1H), 13.94 (brs, 1H), 14.59 (s, 1H); ESIMS found for C23H14FN7 m/z 408.1 (M+H).
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[NH2:18])=[O:7].N1C=CC=CC=1.[C:27](Cl)(Cl)=[O:28].[C:31]1([C:37]2[CH:38]=[CH:39][C:40]3[O:44][C:43]([CH2:45][OH:46])=[CH:42][C:41]=3[CH:47]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[NH:18][C:27]([O:46][CH2:45][C:43]1[O:44][C:40]2[CH:39]=[CH:38][C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:47][C:41]=2[CH:42]=1)=[O:28])=[O:7]
Reactant: C[Si](C)(C)CCOC(=O)c1c(N)ccc2ccccc12
Reactant: O=C(Cl)Cl
Reactant: OCc1cc2cc(-c3ccccc3)ccc2o1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOC(=O)c1c(NC(=O)OCc2cc3cc(-c4ccccc4)ccc3o2)ccc2ccccc12
Temperature: 90 °C

Procedure:
To a solution of 2-amino-naphthalene-1-carboxylic acid 2-trimethylsilanyl-ethyl ester (604 mg, 2.1 mmol) in toluene (12 mL) were added pyridine (0.34 mL, 4.21 mmol) and 20% phosgene in toluene (1.58 mL, 3.04 mmol) under a nitrogen atmosphere. The mixture was heated at 90° C. for 1.5 h, cooled to room temperature and filtered. The filtrate was concentrated to dryness. To the residue were added toluene (12 mL), (5-phenyl-benzofuran-2-yl)-methanol (471 mg, 2.10 mmol) and 4-dimethylaminopyridine (26 mg, 0.21 mmol) under a nitrogen atmosphere, and the mixture was heated at 90° C. for 16 h. Following dilution with EtOAc, the mixture was washed with 2N HCl, 10% NaHCO3, and brine, dried (Na2SO4) and concentrated to dryness. Purification by chromatography gave 582 mg of 2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-naphthalene-1-carboxylic acid 2-trimethylsilanyl-ethyl ester.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:5]([OH:7])=[O:6])[CH3:3].N1C=CC=C[CH:20]=1.Cl.COC(=O)[C@H](C(C)C)N>C(Cl)(Cl)Cl>[NH:8]([C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C@H:4]([C:5]([O:7][CH3:20])=[O:6])[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: c1ccncc1
Agent: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C

Procedure:
5.61 g of the resin 6a obtained according to Instruction (5b) are stirred in 40 ml of chloroform with 0.50 ml of pyridine and 0.350g of L-valine methyl ester hydrochloride for 130 minutes. The resin is filtered off and washed with 200 ml of chloroform and the filtrate is worked up as described in the previous Example. The yield is 0.300 g of Z-Val-Val-OMe and the melting point of the crude product is 120° C.; according to the IR and NMR spectrum, this product is identical to the authentic comparative preparation.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.Cl.[CH3:14][O:15][C:16]([CH2:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1)=[O:17].[Br:29]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]([CH2:18][C:16]([O:15][CH3:14])=[O:17])[CH2:28][CH2:27]2
Reactant: COC(=O)CC1CCc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCc2cc(Br)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a mixture of aqueous solution of potassium carbonate (30 g) and ethyl acetate was dispersed 2-methoxycarbonylmethyltetrahydroquinoline hydrochloride (24.8 g, 0.1 mol). The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was dissolved in DMF (400 mL) and a solution of N-bromosuccinimide (21.36 g, 0.12 mol)in DMF (400 mL) was added dropwise at 0° C. The mixture was stirred for 5 h at room temperature, poured into water (250 mL), and extracted with ether (250 mL). The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give 36 g of the crude title compound (quant) which was used for the next step without purification. The specimen for characterization was obtained by silica gel column chromatography of the crude compound with 1:1 dichloromethane/hexane to 100% dichloromethane: 1H NMR (270 MHz, CDCl3) δ7.02~7.06 (m, 2H), 6.38 (dd, 1H, J=1.7, 7.3 Hz), 4.53 (br, 1H), 3.75 (s, 3H), 3.72~3.75 (m, 4H), 2.70~2.85 (m, 2H), 2.49~2.53 (m, 1H), 1.89~1.99 (m, 1H), 1.61~1.75 (m, 1H),
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH2:12][C:13]([OH:15])=[O:14].[BH4-].[Na+].O>C(O)C>[OH:11][CH:10]1[CH2:9][CH2:8][C@H:7]([CH2:12][C:13]([OH:15])=[O:14])[C@H:6]1[CH2:5]/[CH:4]=[CH:3]\[CH2:2][CH3:1]
Reactant: CC/C=C\CC1C(=O)CCC1CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC/C=C\C[C@H]1C(O)CC[C@@H]1CC(=O)O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
In a 50 ml three-necked flask equipped with a condenser, a thermometer and a magnetic stirrer, 1 g (4.8 mmol) of (+/−)-jasmonic acid was dissolved in 15 ml of absolute ethanol. 430 mg (11.4 mmol) of sodium borohydride, NaBH4, were added. The mixture was stirred at 50° C. for 4 hours. When the reaction was finished, 5 ml of water were added slowly. The precipitate formed was filtered off. The filtrate was acidified to pH=5 with hydrochloric acid and then extracted with ethyl acetate (3×30 ml). The organic phase was dried over sodium sulphate, filtered on filter paper, and then concentrated. The colourless oil obtained was purified by chromatography on silica gel (eluent: dichloro-methane/methanol). The colourless oil obtained was dried under vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cccnc3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:9][CH:10]([CH2:13][SH:14])[CH2:11][OH:12]>>[OH:12][CH2:11][CH:10]1[CH2:13][S:14][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:9]1
Reactant: OCC(S)CS
Reactant: O=Cc1ccccc1
Product: OCC1CSC(c2ccccc2)S1

Procedure:
According to the procedure of Example 1, 35 g. (0.33 mole) of benzaldehyde and 40 g. (0.33 mole) of 2,3-dimercaptopropanol were reacted to yield 63.6 g. of crude product. After recrystallization 42.4 (56%) of the desired product were obtained as shown by nmr spectroscopy.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[F:13][C:14]([F:19])([F:18])[CH:15]1[O:17][CH2:16]1>>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([NH:7][CH2:16][CH:15]([OH:17])[C:14]([F:19])([F:18])[F:13])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: FC(F)(F)C1CO1
Product: OC(CNc1cccc(OC(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Yield: 88.5 %

Procedure:
EX-321A) 3-Trifluoromethoxyaniline (23.81 g, 134.4 mmol) and 3,3,3-trifluoro-1,2-epoxypropane (3.76 g, 33.6 mmol) were placed into a sealed tube and heated to 80° C. for 24 h. The excess aniline was removed by distillation (70° C. at 16.2 Torr) to give 8.6 g (88%) of the desired 3-[(3-trifluoromethoxyphenyl)amino]-1,1,1-trifluoro-2-propanol product as a light yellow oil. 1H NMR (CDCl3) δ3.29-3.37 (m, 1H), 3.55 (dd, 1H), 4.20 (m, 1H), 6.48-6.63 (m, 3H), 7.12 (t, 1H). 19F NMR (CDCl3) δ−79.36 (s, 3F), −58.44 (s, 3F).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)(=[O:15])=[O:14].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[O:14]=[S:13]1(=[O:15])[C:16]2=[CH:17][N:18]=[CH:19][CH:20]=[C:21]2[C:22](=[O:24])[N:12]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: O=C(O)c1ccncc1S(=O)(=O)NCCCCOC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccncc2S(=O)(=O)N1CCCCOC1CCCCO1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a stirred solution of 19 g of N-(4-(2-tetrahydropyranyloxy)butyl) 4-carboxypyridine-3-sulfonamide and 16 mL of triethylamine in 300 mL of dichloromethane at 0° C. was added 6.5 mL of methyl chloroformnate dropwise. After 30 min, the mixture was shaken with 100 mL of saturated sodium bicarbonate, dried over MgSO4 and concentrated under reduced pressure. Chromatography of the dark brown oil over silica gel, eluting with 1:1 ethyl acetate:hexane gave 16 g of homogeneous 1,1-dioxido-2-(4-(2-tetrahydropyranyloxy) butyl)-isothiazolo[5,4-c]pyridin-3(2H)-one as an amber oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.[Cl-].[NH4+:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH2:31])=[O:23])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: COCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: [NH4+]
Agent: [Cl-]
Product: COCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(N)=O)c2n1
Yield: 55 %

Procedure:
Prepared by the method described in Example 76, Step F using (R)-5-(2-(5-fluoro-2-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and ammonium chloride to yield the title compound as a white solid (32.6 mg, 55% yield). MS (apci) m/z=400.1 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([O:25]C)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].CC(C)([O-])C.[K+]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:18][CH2:19][S:20][CH2:21][CH2:22]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCSCC3)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 4A, 3.00 g (7.97 mmol) of the compound from Example 46A and 8.94 g (79.7 mmol) of potassium tert-butoxide were reacted. The reaction led selectively to the cis isomer. Yield: 2.74 g (93% of theory)
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl-].[Na+].O>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ncccc1F
Temperature: 145 °C
Yield: 98.8 %

Procedure:
A mixture of diethyl 2-(3-fluoropyridin-2-yl)malonate (2.68 g, 10.5 mmol), sodium chloride (0.675 g, 11.6 mmol) and water (0.378 mL, 21.0 mmol) in DMSO (15 mL) was heated at 145° C. for 4.5 h. The mixture was cooled, diluted with EtOAc and washed sequentially with water and brine. The organic phase was dried and concentrated to provide ethyl 2-(3-fluoropyridin-2-yl)acetate as a pale colored oil (1.90 g, 99% yield) which was used without further purification. Mass spectrum m/z 184 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([Cl:16])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.N#N.Cl[Sn](Cl)(Cl)Cl.ClC[CH:26]([O:29]C(CCl)CCl)CCl.Cl>O.C(Cl)Cl>[Cl:1][C:2]1[C:15]2[C:6](=[C:7]([CH:26]=[O:29])[C:8]3[C:13]([CH:14]=2)=[C:12]([Cl:16])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: Clc1cccc2cc3cccc(Cl)c3cc12
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: ClCCl
Solvent: O
Product: O=Cc1c2cccc(Cl)c2cc2c(Cl)cccc12
Yield: 21 %

Procedure:
1,8-Dichloroanthracene prepared by the method of H. O. House et al. (J. Org. Chem. 38 1167 (1973)). A 3 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser, and N2 line was charged with 1,8-dichloroanthracene (17.3 g, 70 mmol) and CH2Cl2 (1500 mL). After further cooling with a salt-ice bath to 5°, SnCl4 (Aldrich, 98%, 36.5 g, 0.14 mol, 16.4 mL), was added in one portion to the reaction. No temperature change occurred. The pot temperature was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 16.09 g, 0.14 mol, 12.60 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to reflux (37°). Considerable HCl gas evolution occurred during the warming and the early part of the reaction at 37°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt, 100 g) and filtered again and the volume reduced to 100 mL. The clear yellow solution was passed through a 1000 g plug of SiO2 using PhCH3 as the eluting solvent with 500 mL fractions. This chromatography separated unreacted 1,8-dichloroanthracene (11 g, 63%) from the aldehyde and a more polar product. Fractions containing the aldehyde were combined and the PhCH3 removed, to give 5.83 g (21%) of 4,5-dichloro-9-anthracenecarbaldehyde mp 218°-220°, (PhCH3 /CH3OH), (C,H,Cl), (lit. 224°-226°, E. L. Stogryn, J. Med. Chem. 17 563 (1974)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[O:20][C:19]3[CH:18]=[C:17]([OH:21])[CH:16]=[C:15]([OH:22])[C:14]=3[C:12](=[O:13])[CH:11]=2)=[CH:7][C:8]=1[OH:9].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C)C=O.CN(P(N(C)C)(N(C)C)=O)C>[CH2:25]([C:16]1[C:17]([O:21][CH2:12][CH:11]=[CH2:10])=[CH:18][C:19]2[O:20][C:10]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH2:4][CH:3]=[CH2:8])[CH:7]=3)=[CH:11][C:12](=[O:13])[C:14]=2[C:15]=1[O:22][CH2:7][CH:6]=[CH2:5])[CH:26]=[CH2:27]
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: C=CCOc1cc(-c2cc(=O)c3c(OCC=C)c(CC=C)c(OCC=C)cc3o2)ccc1OC
Temperature: 40 °C

Procedure:
12 g of diosmetin in 100 ml of dimethylformamide and 15 ml of HMPA are added very slowly to a suspension of 4.8 g of sodium hydride in 30 ml of dimethylformamide. The mixture is then stirred at 40° C. until the evolution of gas has ceased. 17.25 g of allyl bromide are then added dropwise and the whole is heated at 60° C. for 16 hours, after which the solvents are removed by distillation under reduced pressure. The residue is taken up in dichloromethane and then chromatographed on silica using a 98% dichloromethane/2% methanol mixture as eluant. In that manner a fraction of 7.6 g of compound very fluorescent under 366 nm is recovered. An analytical sample of the title compound is prepared by recrystallisation from isopropanol, m.p.: 107° C.