Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C[C:12]([O-])=[O:13].[Na+].C=O>CC(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:12][OH:13])=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2nccn2n1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1cnc2ccc(Cl)nn12
Yield: 72.3 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine (1.5 g, 9.8 mmol) in AcOH (50 mL) was added NaOAc (1.4 g, 17.1 mmol) and paraformaldehyde (1.5 g). The mixture was heated at reflux overnight and concentrated under reduced pressure. The residue was basified to pH 12. Then the mixture was filtered and the solid was washed with EtOH to afford (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-methanol (1.3 g) in 72% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][C:4]=2[N:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1>CCOCC>[ClH:1].[Cl:1][C:2]1[C:3]2[CH2:15][CH2:14][NH:13][CH2:12][C:4]=2[N:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Solvent: CCOCC
Product: Cl
Product: FC(F)(F)c1nc(Cl)c2c(n1)CNCC2
Yield: 189.7 %

Procedure:
4-Chloro-7-(phenylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (262 mg, 0.80 mmol) was debenzylated following a procedure similar to that described in Example 3, Step B. Trituration with ether gave 208 mg (95%) of the title compound as an off-white solid. LC-MS 238.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][O:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][O:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: FC(F)(F)c1ccc(Cl)c(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c1

Procedure:
Using 2-chloro-5-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 133. 1H NMR(CDCl3) δ: 9.45 (broad s, 1H), 9.20 (broad s, 1H), 7.68 (s, 1H), 7.52-7.45 (m, 2H), 6.41 (d, 1H, J=2.2 Hz), 6.27 (d, 1H, J=2.2 Hz), 4.55 (ABq, 2H, JAB=14.3 Hz), 4.40 (s, 2H), 4.22 (app d, 1H, J=12.8 Hz), 3.69 (app t, 1H), 3.53-3.38 (m, 2H), 3.35-3.10 (m, 4H), 2.70-2.50 (m, 2H), 2.23-2.10 (m, 2H).
Reaction SMILES: [BH4-].[Na+].C(=[C:10]1[CH:21]=[CH:20][C:13]2[CH2:14][C:15]([NH:17][C:18](=[O:19])[C:12]=2[CH2:11]1)=[O:16])C1C=CC=CC=1.O>CO>[CH2:18]([CH:14]1[C:13]2[C:12](=[CH:11][CH:10]=[CH:21][CH:20]=2)[C:18](=[O:19])[NH:17][CH:15]1[OH:16])[C:12]1[CH:13]=[CH:20][CH:21]=[CH:10][CH:11]=1
Reactant: O=C1CC2=C(CC(=Cc3ccccc3)C=C2)C(=O)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1NC(O)C(Cc2ccccc2)c2ccccc21
Temperature: 25 °C

Procedure:
Sodium borohydride (1.2 g, 32 mmol) was added in portions to a stirred suspension of 4-benzylidenehomophthalimide (2 g, 8 mmol) in methanol (50 ml), then the stirred mixture was heated under reflux for 4 hours, cooled to ambient temperature and added to water (200 ml). The product was extracted into ethyl acetate (3×50 ml), the combined extracts were washed with water (2×30 ml), dried (MgSO4) and the solvent was removed in vacuo. The residue was dissolved in the minimum volume of ether and sufficient hexane was added to precipitate the product. The resulting solid was collected by filtration, washed with hexane (20 ml) and dried in vacuo to give the 4-benzyl-3-hydroxy-3,4-dihydro-1-isoquinolinone intermediate which was used without purification.
Reaction SMILES: [SH2:1].[C:2]([O:6][C:7](=[O:19])[CH:8]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])[N+:9]#[C-:10])([CH3:5])([CH3:4])[CH3:3]>O1CCCC1.[Cu]>[C:2]([O:6][C:7](=[O:19])[CH:8]([NH:9][CH:10]=[S:1])[P:11]([O:13][CH2:14][CH3:15])([O:16][CH2:17][CH3:18])=[O:12])([CH3:4])([CH3:3])[CH3:5]
Reactant: [C-]#[N+]C(C(=O)OC(C)(C)C)P(=O)(OCC)OCC
Reactant: S
Agent: [Cu]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(NC=S)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Dry hydrogen sulphide gas is passed for 10 minutes into a solution, cooled to 0° C., of 277 mg (1 mmol) of diethylphosphono-isocyanoacetic acid tert.-butyl ester in 5 ml of dry tetrahydrofurane (filtered through aluminium oxide). After adding a few crystals of copper-II acetylacetonate, the reaction vessel is closed and left to stand overnight at room temperature. The reaction mixture is filtered and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel thick layer plates with toluene/ethyl acetate, 1:1, and gives thioformamido-diethylphosphonoacetic acid tert.-butyl ester in the form of a colourless oil: IR spectrum (in methylene chloride): characteristic bands at 3.13; 3.35; 5.75; 7.01; 8.10; 8.70 and 9.75μ.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18]CC3C=CC=CC=3)=[CH:15][CH:16]=2)[C:11]([OH:26])=[CH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.C(O)(=O)C.[C].[Pd]>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([OH:26])=[CH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=c1cc(O)c2cc(OCc3ccccc3)ccc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1cc(O)c2cc(O)ccc2n1Cc1ccccc1
Yield: 66.9 %

Procedure:
A solution of the title compound of Step (1) (2.8 g) in a mixture of methanol (180 ml) and acetic acid (75 ml) was hydrogenated at atmospheric pressure in the presence of 10% palladium-carbon (2.0 g) until no further uptake of hydrogen was observed. The reaction mixture was then filtered and the filtrate was evaporated to dryness. The solid residue was crystallized to give the title compound (1.4 g). That the expected product was obtained was confirmed by the spectral data: MS: m/e 267 (M.+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([C:23](OC)=[O:24])[C:19]([F:22])([F:21])[F:20])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][NH2:35]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([C:23]([NH:35][CH3:34])=[O:24])[C:19]([F:20])([F:21])[F:22])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(OC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)C(F)(F)F
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)C(OC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
To a stirring solution of 1,1,1-trifluoro-3-methoxy-3-oxopropan-2-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate (6h) (41 mg, 0.081 mmol) in THF (2 mL) was added methyl amine (0.81 mL, 0.81 mmol, 1.0M in THF). After stirring the reaction mixture for 24 h at room temperature, the reaction was quenched by the addition of aqueous 1N HCl (5 mL) and extracted with dichloromethane (3×, 25 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by SiO2 preparative TLC (50% EtOAc/hexanes) to give the title compound as a colorless oil (30 mg, 73%): 1H NMR 600 MHz (CDCl3) δ 7.31 (d, J=8.50 Hz, 4H), 7.27 (d, J=8.52 Hz, 4H), 6.05 (bs, 1H), 5.48 (q, J=7.10 Hz, 1H), 4.24 (s, 1H), 3.66-3.51 (m, 3H), 3.46 (dd, J=4.67, 15.51 Hz, 1H), 2.89 (d, J=4.90 Hz, 3H), 2.45 (d, J=8.91 Hz, 2H), 2.34 (t, J=16.23 Hz, 2H); HRMS m/z calc'd for [M+H]+ C22H22Cl2F3N3O3: 504.1063. found 504.1065.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]1([CH:22]=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[C:12]1([CH:22]=[C:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1cccc2ccccc12
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCCC(=O)C(=Cc1cccc2ccccc12)C(=O)OCC

Procedure:
A solution of ethyl 3-ketohexanoate (6.6 g), 1-naphthaldehyde (7.34 g), piperidine (1.2 g) and acetic acid (2.25 g) in benzene (50 mL) was heated under reflux for 3 hours and the reaction mixture was dehydrated using a Dean-Stark condenser. The solvent was evaporated and the residue was purified by silica gel column chromatography using an eluent (hexane-ethyl acetate (3:1)) to give ethyl 2-(naphthalen-1-yl)methylene-3-oxohexanoate ((E)/(Z)=1:1 mixture) as a yellow oil. The title compound was obtained as a colorless amorphous solid from ethyl 2-(naphthalen-1-yl)methylene-3-oxohexanoate ((E)/(Z)=1:1 mixture), 3-amino-2-methylpyrazole and p-toluenesulfonic acid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C>C(#N)C.O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(C(c2cccc(C(F)(F)F)c2)N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(C(c2cccc(C(F)(F)F)c2)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of bis(3-(trifluoromethyl)phenyl)methanol (1.1 g, 3.4 mmol) in CH2Cl2 (10 mL) was added dropwise thionyl chloride (0.50 ml, 6.9 mmol) at rt. The reaction was stirred at 50° C. for 4 h, concentrated under vacuum, azeotroped with toluene, and dried under vacuum to give crude chlorobis(3-(trifluoromethyl)phenyl)methane. The crude chlorobis(3-(trifluoromethyl)-phenyl)methane was added to a solution of piperazine (0.81 ml, 10 mmol) in acetonitrile (10 mL), heated to 100° C. for 18 h and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3, filtered, and concentrated to give 1-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazine. The crude 1-(bis(3-(trifluoromethyl)phenyl)-methyl)piperazine was dissolved in acetonitrile (10 mL) and tert-butyl bromoacetate (0.55 mL, 3.4 mmol) and triethylamine (0.96 ml, 6.9 mmol) was added. The solution was stirred for 4 h, diluted with water, and extracted with CH2Cl2. The organic layer was washed with saturated NaCl solution, then dried over Na2SO4, and concentrated. The crude product was purified by ISCO using 0-50% EtOAc in haxanes to give tert-butyl 2-(4-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazin-1-yl)acetate (0.86 g, 50% yield). MS (ESI, pos. ion) m/z: 503.1 (M+1), which was then converted to the title compound by proceeding as described in Example 4 above.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][C:14]#[N:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=[N:26][NH:25]C=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.N#N.[NH2:46][C@@H:47]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C@H:48]([OH:62])[CH2:49][C@@:50]1([C:59]([NH2:61])=[O:60])[CH2:54][CH2:53][CH2:52][N:51]1[C:55]([CH3:58])([CH3:57])[CH3:56]>CN(C)C=O.ClCCl>[N:25]#[N:26].[OH2:8].[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([NH:46][C@@H:47]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C@H:48]([OH:62])[CH2:49][C@@:50]1([C:59]([NH2:61])=[O:60])[CH2:54][CH2:53][CH2:52][N:51]1[C:55]([CH3:58])([CH3:56])[CH3:57])=[O:18])[CH2:13][C:14]#[N:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([NH:46][C@@H:47]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C@H:48]([OH:62])[CH2:49][C@@:50]1([C:59]([NH2:61])=[O:60])[CH2:54][CH2:53][CH2:52][N:51]1[C:55]([CH3:58])([CH3:56])[CH3:57])=[O:17])[CH2:13][C:14]#[N:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@@H](N)Cc1ccccc1)C(N)=O
Reactant: N#CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC#N)NC(=O)OCc1ccccc1)C(N)=O
Product: O
Temperature: 25 °C
Yield: 23.4 %

Procedure:
0.122 g of N-(benzyloxycarbonyl)-3-cyano-L-alanine was dissolved in 2 ml of dry dimethylformamide. The solution was stirred and cooled in an ice/salt bath and treated with 0.066 g of hydroxybenzotriazole and 0.1 g of dicyclohexylcarbodiimide. The mixture was stirred for 5 minutes and then treated with 0.163 g of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide in 2.5 ml of dry dichloromethane. The mixture was allowed to warm to room temperature and was then stirred overnight. The resulting dicyclohexylurea was filtered off and washed with methylene chloride. The combined filtrate and washings were evaporated at 40° C. in a vacuum to give an oil which was partitioned between ethyl acetate and water. The organic phase was washed in sequence with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution and then dried over sodium sulphate. The solvent was removed by evaporation to give an oil which was chromatographed on silica gel using 14% methanol in dichloromethane for the elution. There were thus obtained 50 mg of product which was recrystallized from diethyl ether/n-hexane to give 0.045 g of N2 -[3(S)-[[N-(benzyloxycarbonyl)-3-cyano-L-alanyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide hemihydrate as a solid of melting point 65°-70° C. (softening).
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:20][S:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]12[CH2:18][O:17][C:14]([CH3:19])([O:15][CH2:16]1)[O:13][CH2:12]2.[CH:32]1(C23OCC(CO)(CO2)CO3)C[CH2:33]1>>[Na:1].[CH:19]1([C:14]23[O:15][CH2:16][C:11]([CH2:10][O:9][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([CH2:20][S:21]([C:23]5[NH:24][C:25]6[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=6[N:27]=5)=[O:22])[C:3]=4[CH3:2])([CH2:12][O:13]2)[CH2:18][O:17]3)[CH2:33][CH2:32]1
Reactant: OCC12COC(C3CC3)(OC1)OC2
Reactant: Cc1c(OCC23COC(C)(OC2)OC3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [Na]
Product: Cc1c(OCC23COC(C4CC4)(OC2)OC3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 3.2 %

Procedure:
The same procedure as in the steps (24b) to (24f) of Example 24 was repeated using (1-cyclopropyl-2,6,7-trioxabicyclo[2.2.2]oct-4-yl)methanol obtained in the step (37c) above to obtain the title compound (147 mg, total yield: 3.2%) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Br)nc1
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1nc(Br)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a suspension of 6-bromopyridin-3-ol (2.5 g, 14.4 mmol) in acetic acid (20 mL) at 0° C. was added fuming nitric acid (0.9 mL, 22.4 mmol). The reaction mixture was stirred at room temperature for 1 hour and then at 60° C. for 1 hour. The reaction mixture was cooled to 0° C. and 10M aqueous hydroxide was added dropwise until pH 4-5 (ca 25 mL). The resulting mixture was diluted with water and partially concentrated under reduced pressure. The residue was extracted twice with EtOAc. The organic fractions were combined and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was azeotroped with toluene to give 6-Bromo-2-nitropyridin-3-ol as an orange solid (2.2 g, 71%). 1H NMR (400 MHz, DMSO-d6): δ 11.92 (s, 1 H); 7.86-7.83 (d, J=8.6 Hz, 1 H); 7.61 (d, J=8.6 Hz, 1 H).
Reaction SMILES: [Zn:1].[OH2:2].[F:3][CH:4]([F:9])[S:5](Cl)(=[O:7])=[O:6]>[Al]>[F:3][CH:4]([F:9])[S:5]([O:7][Zn:1][O:2][S:5]([CH:4]([F:9])[F:3])=[O:6])=[O:6]
Reactant: [Zn]
Reactant: O
Reactant: O=S(=O)(Cl)C(F)F
Agent: [Al]
Product: O=S(O[Zn]OS(=O)C(F)F)C(F)F
Temperature: 0 °C
Yield: 81.6 %

Procedure:
To a vessel equipped with a stir bar, Zn dust (1.8 g, 27.8 mmol) was added H2O (20 mL). The reaction vessel was then capped, wrapped in aluminum foil and cooled in an ice bath to 0° C. Difluoromethanesulfonyl chloride (5 g, 33.3 mmol) was then added via syringe open to air. The reaction vessel was sealed with cap and the reaction mixture was removed from the ice bath and allowed to warm to room temperature over 2 h. The excess Zn was removed via filtration, washed with EtOAc (3×10 mL), the filtrate was concentrated under reduced pressure. Residual water was removed azeotropically with toluene (3×10 mL) at 45° C., and the resulting pearly yellow powder was further dried under vacuum for an additional 3 h to give bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) (4 g, yield: 81.6%), which was used in the next step without purification. 1H NMR (DMSO-d6 400 MHz) δ 5.24 (t, J=56.0 Hz, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1.[H-].[Na+].[CH3:15][C:16]1([CH3:24])[CH2:20][O:19][CH2:18][N:17]1[C:21](Cl)=[O:22].O>O1CCCC1.CN(C)C=O>[CH3:15][C:16]1([CH3:24])[CH2:20][O:19][CH2:18][N:17]1[C:21]([N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1)=[O:22]
Reactant: CC1(C)COCN1C(=O)Cl
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COCN1C(=O)n1nnc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
A solution of 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (3 g, 18.39 mmol) in a mixture of tetrahydrofuran (90 mL) and dimethylformamide (50 mL) was added dropwise to a stirred suspension of sodium hydride (1.839 g, 46 mmol) in tetrahydrofuran (30 mL) at 0° C. The suspension was allowed to stir at room temperature for 30 minutes before adding dropwise, at 0° C., a solution of 4,4-dimethyloxazolidine-3-carbonyl chloride (3.16 g, 19.31 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to stir at room temperature for 4 h. Water was added at 0° C. and the solvent was evaporated. A mixture of dichloromethane/isopropanol (7:3) was added and the organic layer was separated. The aqueous layer was re-extracted with dichloromethane and the combined organic layers were dried (MgSO4), filtered and evaporated. The orange residue was recrystallised from isopropanol to give a beige solid (840 mg) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:19][CH2:20][C:21](Br)=[O:22]>C1COCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:21](=[O:22])[CH2:20][Br:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: O=C(Br)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CBr)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-benzyl-2-oxazolidinone in dry THF (300 ml) was stirred at −78° C. under nitrogen during the dropwise addition of 1.6 M n-butyl lithium in hexanes, (60 ml, 97 mmol) followed by bromo-acetyl bromide. The pale yellow solution was stirred for a further 10 minutes at −78° C. and allowed to warm to room temperature over 30 minutes. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution. After dilution with ethyl acetate and brine, the two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo to give 4-benzyl-3-(2-bromo-acetyl)-oxazolidin-2-one (26.2 g) which was used in the next step without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=O)=O.[CH3:16][NH2:17]>>[CH3:16][NH:17][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CS(=O)(=O)OCCC#Cc1ccccn1
Reactant: CN
Product: CNCCC#Cc1ccccn1
Temperature: 45 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
4-(Pyridin-2-yl)but-3-ynyl methanesulfonate (2.90 g, 12.87 mmol) was dissolved in methylamine 40% in aqueous solution (20 mL) and stirred for 3 hours under nitrogen at 45° C. The reaction mixture was cooled with ice, quenched with water and extracted with DCM. The organic phases were washed with brine, dried over MgSO4 and concentrated. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, DCM/MeOH: from 90/10 to 90/10 with 1% of TEA as eluent) to afford 817 mg N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (Yield: 39%) as a brown oil
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:16]([O:20][C:21]([NH:23][CH:24]([CH2:37][C:38]1([F:43])[CH2:42][CH2:41][CH2:40][CH2:39]1)[C:25]([NH:27][C:28]1([CH:32]([OH:36])[C:33](O)=[O:34])[CH2:31][CH2:30][CH2:29]1)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][CH:24]([C:25](=[O:26])[NH:27][C:28]1([CH:32]([OH:36])[C:33](=[O:34])[NH:1][C:2]2[CH:6]=[CH:5][NH:4][N:3]=2)[CH2:31][CH2:30][CH2:29]1)[CH2:37][C:38]1([F:43])[CH2:42][CH2:41][CH2:40][CH2:39]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1cc[nH]n1
Reactant: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)O)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)Nc2cc[nH]n2)CCC1
Temperature: 0 °C
Reaction time: 0.04 h
Yield: 62.8 %

Procedure:
3-Aminopyrazole (92 mg, 1.08 mmol) and DIEA (110 μL, 1.08 mmol) were added to a solution of compound 57-b (0.31 mmol) in anh. DMF (3 mL). The solution was cooled to 0° C. and stirred for 2-3 minutes, then HATU (126 mg, 0.32 mmol) in anh. DMF (1 mL) was added. The reaction mixture was allowed to attain room temperature, stirred for 16 h and then diluted with DCM. The organic phase was extracted with NaHCO3 sat. aq. solution. The aqueous phase was extracted with ethyl acetate and the combined organics dried over anh. Na2SO4 and then concentrated. Purification by flash column chromatography (MeOH/DCM, 0:1-2:8) gave the title compound (91 mg g, 63%). MS m/z 468.3 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][C:33]=1[CH2:41]O)[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH2:41][C:33]4[CH:34]=[C:35]([O:38][CH2:39][CH3:40])[CH:36]=[CH:37][C:32]=4[O:31][CH2:29][CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOc1ccc(OCC)c(CO)c1
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1ccc(OCC)c(COc2cc(-n3cnc4cnc(CO[Si](C)(C)C(C)(C)C)cc43)sc2C(=O)OC)c1

Procedure:
In a similar manner as described for example B31, 1.5 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 0.91 g of (2,5-diethoxyphenyl)methanol, 2.4 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 1.66 g of di-tert-butyl azodicarboxylate in 40 ml anhydrous dichloromethane yield the title compound.