Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:23])=[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17](OCC)=[O:18])[C:11]=2[CH3:22])[CH:9]=1)[CH3:2].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:23])=[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH2:17][OH:18])[C:11]=2[CH3:22])[CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1nc(C)cc(-c2cc(OCC)ccc2F)c1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(F)c(-c2cc(C)nc(CO)c2C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a stirred solution of ethyl 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carboxylate (which may be prepared as described in Description 139) (5.51 g, 17.36 mmol) in absolute ethanol (45 mL) under nitrogen at 25° C., was added sodium borohydride (3.28 g, 86.81 mmol) in portions over 40 min. The resulting mixture was left to stir for another 3 h. It was treated with crushed ice (80 mL) and the pH was carefully adjusted to 7 with the addition of 2M HCl. The reaction mixture was extracted with DCM and the organic layers were washed with brine then collected by passing down a PhaseSep cartridge. Evaporation of the volatiles gave [4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl]-methanol (D140) (4.33 g, 15.727 mmol, 90.6% yield) as colourless oil;
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To the product of Example 5 (0.35 g, 0.0006 mole) in H2O (40 ml) and CH3CN (5 ml) was added LiOH (70 mg, 0.0017 mole). The reaction mixture was stirred at room temperature for 1 hour. The pH was lowered to ≃4.5 with TFA and the product was isolated by RPHPLC to yield (±)β-[[2-[[[3-[(aminoiminomethyl)-amino]phenyl]carbonyl]amino]acetyl]amino]-1,3-benzodioxole-5-propanoic acid, trifluoroacetate salt (280 mg) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2)(=[O:25])[CH3:24]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 19-hydroxyandrost-4-ene-3,17-dione in acetic anhydride and pyridine is allowed to stand overnight after which the reaction mixture is poured into ice water. The resulting solid is collected, dried and recrystallized from hexane to give 19-acetoxyandrost-4-ene-3,17-dione.
Reaction SMILES: I[C:2]([F:11])([F:10])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])I.I[C:13]1[CH:14]=[C:15]([C:21]#[N:22])[C:16](=[CH:19][CH:20]=1)[C:17]#[N:18].CS(C)=O>[Cu].O>[C:21]([C:15]1[CH:14]=[C:13]([C:2]([F:11])([F:10])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]#[N:22])[CH:14]=2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])#[N:22]
Reactant: FC(F)(I)C(F)(F)C(F)(F)I
Reactant: N#Cc1ccc(I)cc1C#N
Agent: [Cu]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(C(F)(F)C(F)(F)C(F)(F)c2ccc(C#N)c(C#N)c2)cc1C#N
Yield: 54.4 %

Procedure:
1, 3-Diiodoperfluoropropane (2.0 g, 5 mmol), 1.8 g (30 meq) of activated copper, 2.5 g (10 mmol) of 4 - iodophthalonitrile and 6 ml of dry dimethyl sulfoxide were purged for 15 minutes with argon and the mixture was then heated at 115°-120° C. for 4 hours. After cooling, the content was poured into 100 ml of water and extracted with four 50 ml portions of ether. The combined ethereal extract was washed with water, charcoaled, dried over anhydrous sodium sulfate and concentrated at reduced pressure to afford 1.1 g (52%) of product, m.p. 133°-135° C.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[N:19]=[C:20]([I:21])[C:13]=12>ClCCl>[I:21][C:20]1[C:13]2[C:14](=[N:15][CH:16]=[N:17][C:12]=2[NH2:11])[N:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(I)nn2C1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 250 mL) was added to a solution of tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (10.72 g, 24.1 mmol) in dichloromethane (100 mL) at 0° C. 15 minutes later, the ice-bath was removed and the reaction mixture was stirred at room temperature for 5 hours. The solvents were evaporated and the residue was dissolved in dichloromethane. Hydrochloric acid (5.0N) was added and the aqueous layer was washed with dichloromethane three times. Sodium hydroxide (50%) was added to adjust the pH to about 10. The suspension was lyophilized to reduce the volume to one third of the original volume. The solid was collect by filtration to give 3-iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (8.109 g, 97%). 1H NMR (CDCl3) δ 1.81 (m, 2H), 1.99 (m, 2H), 2.65 (m, 2H), 3.07 (m, 2H), 4.68 (m, 1H), 8.19 (s, 1H).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]#[N:17]>O.C(O)(=O)C>[C:16]([CH2:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([NH:5][C:2]([NH2:3])=[O:1])[CH:7]=2)[NH:11][CH:10]=1)#[N:17]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1c[nH]c2ccc(NC(N)=O)cc12
Yield: 16 %

Procedure:
A solution of sodium cyanate (1.2 g) in water (10 ml) was added to a stirred solution of 5-amino-1H-indole-3-aceto-nitrile (1.5 g) in glacial acetic acid (5 ml) and water (10 ml). Stirring was continued until a brown gum precipitated (10 min). The aqueous layer was then decanted off, and extracted with ethyl acetate (2×100 ml). The combined extracts were washed with sodium carbonate soln. (2N, 2×100 ml), dried (Na2SO4) and evaporated in vacuo to yield the crude urea as an off-white solid (0,3 g). The brown gum was purified by column chromatography (Kieselgel 60, 25 g) using ethyl acetate as eluant to yield more of the crude urea (0.1 g). The crude urea was then crystallised from isopropanol to yield the title compound as a fawn solid (0.3 g) m.p. 200°-204°.
Reaction SMILES: [OH-].[Li+].C([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12](C(=O)C)[N:11]=[CH:10]2)(=O)C.S([O-])(O)(=O)=O.[K+].O>CO.O1CCCC1>[CH3:16][C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][C:7]=1[OH:6]
Reactant: CC(=O)Oc1cc2cnn(C(C)=O)c2cc1C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2[nH]ncc2cc1O
Reaction time: 1 h
Yield: 92 %

Procedure:
A 2M-aqueous lithium hydroxide solution (1.46 ml, 2.93 mmol) was added dropwise to a solution of 1-acetyl-6-methyl-1H-indazol-5-yl acetate (340 mg, 1.46 mmol) in a mixture of methanol (2.0 ml) and tetrahydrofuran (1.0 ml) at room temperature. After 1 hour, the reaction mixture was adjusted to pH 4 with a 0.5M-aqueous potassium hydrogensulfate solution. The resulting solution was poured into water (50 ml) and extracted with ethyl acetate (30 ml×3), and the extract solution was dried over anhydrous magnesium sulfate. The extract solution dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 6-methyl-1H-indazol-5-ol (199 mg, 92%).
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[C:19]2=[N:20][CH:21]=[C:22]3[CH:26]=[N:25][N:24]([CH3:27])[C:23]3=[C:18]2[CH:17]=[C:16]1[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]([CH3:39])[CH:29]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][N:15]1[C:19]2=[N:20][CH:21]=[C:22]3[CH:26]=[N:25][N:24]([CH3:27])[C:23]3=[C:18]2[CH:17]=[C:16]1[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]([CH3:39])[CH:29]=1)=[O:2]
Reactant: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1COP(=O)(OC(C)(C)C)OC(C)(C)C)cnn4C)cn2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1COP(=O)(O)O)cnn4C)cn2C
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
Di-tert-butyl (7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methylpyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)methyl phosphate (0.486 g, 0.878 mmol) was dissolved in DCM (10 mL) then TFA (1.00 mL, 13.0 mmol) was added. The mixture was stirred 10 min then concentrated under reduced pressure. The material was dissolved in DMF (12 mL) and the material was purified by preparative reverse phase HPLC (Table 2, Method i). The fractions containing the title compound were collected then concentrated under reduced pressure to remove most of the MeCN. The solid was collected by filtration and washed with water (0.5 mL). The solid was dried to constant weight at about 60° C. under vacuum to give (7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methylpyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)methyl dihydrogen phosphate (0.165 g, 43%): LC/MS (Table 2, Method a) Rt=1.58 min; MS m/z 442 (M+H)+. Syk IC50=C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[O:22]([CH2:29][CH2:30][NH2:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[NH:31][CH2:30][CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-:14])=[O:13]
Reactant: NCCOc1ccccc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCOc3ccccc3)cc2c1=O
Yield: 52 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 2-phenoxy-ethylamine according to the GPA affording 14 mg (52%) of a red powder. Rt=5.25 min.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]=[O:7].[CH:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10]>C(=O)=O.CC(C)=O>[CH:8]([O:17][CH2:6][O:7][CH:8]([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: C=O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: FC(F)(F)C(OCOC(C(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 300 ml reactor, which had been cooled down in dry ice/acetone bath to -20° C., was charged with 111.3 g of fuming sulfuric acid, 9.3 g of paraformaldehyde and 52.8 g of HFIPA, followed by stirring for 20 minutes. After stopping stirring, it was cooled down to room temperature by standing still. With this, the contents were separated into two layers. The organic matter of the upper layer was taken out and then washed with 50 ml of 5% sodium hydrogencarbonate aqueous solution. With this, it was separated into two layers to obtain an organic matter.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[S:4][N:3]=1.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[S:4][N:3]=1
Reactant: Cc1nsc(-c2ccc([N+](=O)[O-])cc2)n1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nsc(-c2ccc(N)cc2)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 136 %

Procedure:
To a suspension of 3-methyl-5-(4-nitro-phenyl)-[1,2,4]thiadiazole (104 mg, 0.423 mmol, CAS 800408-77-9) in ethanol (4.3 mL) was added tin(II) chloride (401 mg, 2.1 mmol) and the reaction was heated to 70° C. for 4 hours. The yellow solution was poured onto saturated aqueous sodium hydrogen carbonate solution and the mixture was stirred for 30 minutes. The precipitate was filtered off, washed with water. The solid was heated 3 times with tetrahydrofurane and filtered. The collected organic layers were evaporated to yield crude title compound (110 mg, quant.) as a yellow solid. MS ISP (m/e): 192.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.64 (d, 2H), 6.63 (d, 2H), 6.01 (br s, 2H), 2.54 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:35][CH:34]=1)[C:3]([NH:5][C@H:6]([C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si](C)(C)C)=[CH:22][C:21]=2[F:32])=[CH:18][N:19]=1)[C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[NH2:1][CH:2]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[CH:35][CH:34]=1)[C:3]([NH:5][C@H:6]([C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][C:21]=2[F:32])=[CH:18][N:19]=1)[C@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])=[O:4]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)C(N)c1ccc(OCCOC(C)(C)C)cc1)c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2F)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1ccc(-c2cnc([C@@H](NC(=O)C(N)c3ccc(OCCOC(C)(C)C)cc3)[C@@H](C)c3ccccc3)[nH]2)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of 2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-N-{(1S,2S)-1-[5-(2-fluoro-4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-acetamide (290 mg, 0.45 mmol) in tetrahydrofuran (10 mL) at room temperature under an atmosphere of nitrogen was added 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (680 μL, 0.68 mmol) and the resulting solution was allowed to stir for 2 hours. The reaction was poured into ethyl acetate (50 mL), washed with water (2×20 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-N-{(1S,2S)-1-[5-(4-ethynyl-2-fluoro-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-acetamide which was used without further purification (250 mg, 97%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=2[O:25]1>>[O:25]1[C:26]2[CH:27]=[CH:28][C:29]([C:6]3[N:7]=[C:8]([N:10]4[C:14]5[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=5[N:12]=[CH:11]4)[S:9][C:5]=3[C:3]([OH:2])=[O:4])=[CH:30][C:31]=2[O:32][CH2:24]1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: COc1cc2ncn(-c3nc(-c4ccc5c(c4)OCO5)c(C(=O)O)s3)c2cc1OC
Yield: 24.7 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3,4-methylenedioxybenzeneboronic acid (24.9 mg, 0.15 mmol) gave 4-Benzo[1,3]dioxol-5-yl-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (10.5 mg, 25%) as a white solid. MS m/z 426 (M+1).
Reaction SMILES: [Cl:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16]C)=[O:14])=[C:5](O)[CH:4]=1.[OH-].[K+].Cl.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:34]>C(O)C.O>[Cl:34][C:5]1[CH:4]=[C:3]([C:2]([Cl:1])([F:20])[F:19])[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1cccc(C)n1
Solvent: CCO
Solvent: O
Product: COC(=O)c1c(Cl)cc(C(F)(F)Cl)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.3 %

Procedure:
A mixture of 5.0 g (0.016 mol) of product of Example 5, 8.38 g (0.154 mol) of KOH, 45 ml of water in 100 ml of ethanol were refluxed for 16 hours. The reaction mixture was poured into 250 ml of water containing 50 ml of HCl, extracted with ether, dried (MgSO4) and concentrated in vacuo to 3.35 g of solid. Then 45 ml of SOCl2 was added to the solid and this was refluxed for 2 hours. Reaction mixture was concentrated in vacuo and 45 ml of methanol was added to the residue and refluxed for 16 hours. Reaction mixture was concentrated in vacuo. The residue was dissolved in ether, extracted with 10% K2CO3, and water. The combined aqueous layers were acidified with concentrated HCl, extracted with ether, dried (MgSO4) and concentrated in vacuo to 2.11 g of white solid. To this solid was added 1.21 ml (0.010 mol) of 2,6 -lutidine and 20 ml of POCl3. This was refluxed for 16 hours. The reaction mixture was concentrated in vacuo. The residue was poured into water, extracted with ether, washed with 10% HCl, dried (MgSO4) and concentrated in vacuo to 2.17 g of brown oil. Then 50 ml of MeOH was added and this was refluxed for 31/2 hours and then stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo to 1.88 g of crude produt. Kugelrohr distillaton at 47 Pa, pot temperature 80° C., afforded 1.55 g (68.3%) of product as a clear oil, nD25 1.4493.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2nc(-c3cncc(Br)c3)sc2c1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc2nc(-c3cccnc3)sc2c1O
Temperature: 25 °C
Yield: 39 %

Procedure:
A mixture of 2-(5-bromo-pyridin-3-yl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (88 mg, 0.23 mmol), ammonium formate (296 mg, 4.63 mmol) and 10% Pd/C (114 mg) in ethyl acetate (7 mL) was refluxed for 21 h before it was cooled to room temperature and filtered. The filtrate was washed with saturated sodium bicarbonate, water, dried and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of methanol and dichloromethane dried in vacuo to give the title compound as a yellow solid (27 mg): MS: (+) m/z 302.07 (M+1); (−) m/z 300.27 (M−1).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[F:14][C:15]1([F:28])[CH2:20][CH2:19][C:18]([CH2:26]O)([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1>>[F:14][C:15]1([F:28])[CH2:20][CH2:19][C:18]([CH2:26][F:11])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: CCOC(=O)C1(CO)CCC(F)(F)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Product: CCOC(=O)C1(CF)CCC(F)(F)CC1
Temperature: 70 °C

Procedure:
A neat stirred mixture of Deoxo-Fluor® (196 mg, 0.887 mmol) and ethyl 4,4-difluoro-1-(hydroxymethyl)cyclohexanecarboxylate (98.6 mg, 0.444 mmol) was heated at 70° C. overnight. The reaction was cooled to rt and quenched with ice and extracted with DCM, washed with satd. NaHCO3, water, brine and dried (MgSO4). Evaporation of DCM gave a light brown oil which was purified by silica gel FCC (1:3 hexanes:DCM) to afford ethyl 4,4-difluoro-1-(fluoromethyl)cyclohexanecarboxylate as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.42 (d, J=47.2 Hz, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.33-2.19 (m, 2H), 2.15-2.01 (m, 2H), 2.01-1.81 (m, 2H), 1.69-1.56 (m, 2H), 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CN1CCCC1=O.[OH:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][NH2:24]>C(N(CC)CC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][OH:27])[CH2:20][CH2:19][OH:18])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCN(CCO)CCO
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCCN(CCO)CCO)cc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
5 g of para-fluoronitrobenzene were added to a solution of 60 ml of N-methylpyrrolidinone, 6.29 g of N,N-bis(2-hydroxyethyl)ethylenediamine, and 4.3 g of triethylamine. The reaction medium was heated at 60° C. for 15 hours and, after cooling to room temperature, was poured into a water/ice mixture. A yellow precipitate formed, which was filtered off, reslurried in water, and then dried over P2O5. 7.5 g of 2-[[2-(4-nitrophenylamino)ethyl]-(2-hydroxyethyl)amino]ethanol (19) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:6]2.[H-].[Na+].CN(C)C=O.[CH3:26][O:27][CH2:28]Cl>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:6]2[CH2:26][O:27][CH3:28]
Reactant: COCCl
Reactant: CCOC(=O)c1cc2c(F)ccc([N+](=O)[O-])c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(F)ccc([N+](=O)[O-])c2n1COC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A mixture of ethyl 4-fluoro-7-nitro-1H-indole-2-carboxylate (0.48 g), 60% sodium hydride (0.12 g) and N,N-dimethylformamide (20 mL) was stirred at 4° C. for 30 min. A solution (5 mL) of chloromethyl methyl ether (0.25 mL) in tetrahydrofuran was added dropwise under ice-cooling. After stirring at room temperature for 18 hr, the reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5) to give the title compound (0.46 g, yield 81%) as pale-brown needle crystals.
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[C:11]([C:12]([CH3:14])=[CH2:13])=[CH:10][C@@H:9]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[NH:8][CH2:7]1)[CH:2]=[CH2:3].[CH2:24]([O:27]N1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O)C=C>>[CH2:1]([O:4][N:5]1[C:24](=[O:27])[N:8]2[CH2:7][C@H:6]1[C:11]([C:12]([CH3:14])=[CH2:13])=[CH:10][C@H:9]2[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:2]=[CH2:3]
Reactant: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(=C)C
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Product: C=CCON1C(=O)N2C[C@H]1C(C(=C)C)=C[C@H]2CO[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared from O-allyl-N-((3R,6S)-6-((tert-butyldimethylsilyloxy)-methyl)-4-(prop-1-en-2-yl)-1,2,3,6-tetrahydropyridin-3-yl)hydroxylamine (Intermediate 56, 1.22 g, 3.60 mmol) following the procedure described for Intermediate 16. The desired product was obtained as a light yellow oil (1.16 g, 88%).