Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38](=[O:48])[CH2:39][NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:36])([CH3:35])[CH3:34]>ClCCl.C(OCC)(=O)C>[C:33]([O:37][C:38](=[O:48])[CH2:39][N:40]([C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CC(C)(C)OC(=O)CNCc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(=O)c1ccc[nH]1
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylic acid in 75 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0° C. was added 6.96 g (27.0 mmol of BOPCl and 14.1 mL (81.0 mmol) of DIEA. After stirring for 30 minutes, 5.97 g (27.0 mmol) of N-(benzyl)glycine-t-butyl ester was added and the reaction allowed to warn to room temperature overnight. The reaction was diluted with ethyl acetate and washed with a 5% potassium hydrogensulfate, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 100% hexane to (60% hexane/ethyl acetate to afford 2.92 g (34.4%) of the title compound is a white solid. FAB MS [M+H] m/z Calcd: 315, Found: 315.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.[CH3:15][NH:16][O:17][CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a mixture of 5-chloro-1H-indole-2-carboxylic acid (15.0 g), N,O-dimethylhydroxylamine hydrochloride (8.97 g), 1-hydroxybenzotriazole monohydrate (14.1 g), triethylamine (25.6 mL) and N,N-dimethylformamide (200 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17.6 g), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, the resulting precipitate was collected by filtration to give the title object compound (15.5 g, 84%) as a pale-brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])([O:11][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[CH3:9])=[C:4]([F:12])[CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(C)(O)c1ccc(Br)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(OC1CCCCO1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.5 %

Procedure:
To a stirred solution of 2-(4-bromo-2-fluoro-phenyl)-propan-2-ol (18.5 g, 79.4 mmol) and 3,4-dihydro-2H-pyran (10.9 mL, 119.1 mmol) in dichloromethane (165 mL) was added pyridinium-p-toluene sulfonate (2 g, 7.91 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (QingDao silica gel, 200-300 mesh, 25% ethyl acetate/hexanes) to afford 2-[1-(4-bromo-2-fluoro-phenyl)-1-methyl-ethoxy]-tetrahydro-pyran (9.7 g, 38.6%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][NH:10][C:11](=[O:12])[C:3]=12.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16].CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:14][C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[C:3]=12
Reactant: O=C(CCl)N1CCOCC1
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c2c(OCC(=O)N3CCOCC3)nsc2n1
Temperature: 40 °C
Yield: 9.3 %

Procedure:
Pyridinothiazolone 4 (200 mg, 1.22 mmol), was treated with 2-chloro-1-morpholinoethanone (225 mg, 1.25 mmol) and Et3N (370 mg, 3.66 mmol) in anhydrous CH2Cl2 (25 mL) at reflux (40° C.) for 24 h, and then washed with 1 M HCl(aq). The organic phase was dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column with elution of EtOAc/hexane (1:1) to give the title compound (35 mg, 9% yield) in addition to the main N-alkylation product 19 (55%).
Reaction SMILES: I.C[O:3][C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([OH:21])=[O:20].S([O-])(O)=O.[Na+]>C(OC(=O)C)(=O)C>[OH:3][C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COc1c(CC(=O)O)cccc1Oc1ccc(Cl)cc1
Agent: I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C(O)Cc1cccc(Oc2ccc(Cl)cc2)c1O
Temperature: 0 °C
Yield: 69 %

Procedure:
48% Hydriodic acid (40 ml) was added dropwise to a solution of 2-[2-methoxy-3-(4-chlorophenoxy)phenyl]acetic acid (6.7 g) in acetic anhydride (20 ml) with stirring under ice-cooling in 5 minutes, and the mixture was refluxed under heating for 20 minutes. The reaction mixture was poured into an ice-water containing a small amount of sodium hydrogen sulfite and allowed to stand. The precipitating crystals were collected by filtration, washed with water, dried and then recrystallized from a mixture of benzene and n-hexane to give 2-[2-hydroxy-3-(4-chlorophenoxy)phenyl]acetic acid (4.4 g). mp 100°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][N:74]=1)[CH2:65][CH:66]1[CH2:71][CH2:70][CH2:69][CH2:68][NH:67]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:74]1[CH2:75][CH2:76][CH2:77][CH2:78][CH:73]1[CH2:72][N:64]([CH3:63])[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CN(Cc1ccccn1)CC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN(C)Cc3ccccn3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-methyl-N-(piperidin-2-ylmethyl)-pyridin-2-ylmethyl-amine in DMSO at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30](Cl)=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.FC(F)(F)[C@H](C1C(N2C=CC(C)=N2)=[N:46]C(C)=CC=1)O>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:19][CH2:20]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[C:28]([N:34]3[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]3)=[N:46][C:30]([CH3:29])=[CH:31][CH:32]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: Cc1ccc([C@H](O)C(F)(F)F)c(-n2ccc(C)n2)n1
Product: Cc1ccc([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c(-n2ccc(C)n2)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (S)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanol (Intermediate 20)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23]OS(C)(=O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[SH:29][CH2:30][CH2:31][OH:32].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][S:29][CH2:30][CH2:31][OH:32])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: OCCS
Reactant: CS(=O)(=O)OCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1CSCCO
Temperature: 77 °C

Procedure:
Methanesulfonic acid 4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-ylmethyl ester described in Example 10, Step 6 (230 mg, 0.51 mmol) was dissolved in 7.0 mL of methanol and treated with 992 mg (12.7 mmol) of 2-mercaptoethanol and 2.0 mL of 1 M aqueous NaOH. The mixture was heated with a reflux condenser at 77° C. overnight. The mixture was cooled and partitioned between water and DCM. Aqueous phase was extracted with DCM. Combined organic phase was dried over MgSO4 and concentrated. The product was purified by column chromatography using 20% of EtOAc in hexanes as the eluent (140 mg, 63%)
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH3:18].[OH:19]O>C(O)(=O)C>[Cl:1][C:2]1[C:15]2[S:14](=[O:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1ccc2c(c1Cl)Sc1ccccc1N2C
Reactant: OO
Solvent: CC(=O)O
Product: COc1ccc2c(c1Cl)S(=O)c1ccccc1N2C
Temperature: 50 °C

Procedure:
To 4-chloro-3-methoxy-10-methyl-10H-phenothiazine (0.5 g)(see Example 5) was added acetic acid (12 ml) and hydrogen peroxide (2 ml). The reaction mixture was heated at 50° C. for 15 minutes and then, evaporated to dryness. The corresponding sulfoxide (0.5 g) (4-chloro-3-methoxy-10-methyl-5-oxo-10H-phenothiazine) was obtained by crystallization (m.p. decomposed at 141° C.).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH:21]=[CH2:22])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (from Example 1, Step 3) in dioxane (0.15 M) was added tri-n-butyl vinyl tin (1.1 eq.) followed by bis(triphenylphosphine)palladium(II) chloride (0.1 eq.). The reaction was stirred under nitrogen at 100° C. for 3 h and then cooled to RT. The mixture was then diluted with EtOAc and washed with brine (3×). The organic phase was then dried over Na2SO4 and evaporated to dryness. The residual material was purified by chromatography on silica gel (PE:EtOAc, 9:1). The product fractions were evaporated and the residual material re-crystallised from DCM with PE. The product was obtained as yellow crystalline material (60%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.ClC(OC)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CC(C)=O.O>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:32]=[N+:33]=[N-:34])=[O:16])=[CH:13][CH:12]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: [N-]=[N+]=[N-]
Agent: COC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCCCc1cnc(-c2ccc(C(=O)N=[N+]=[N-])cc2)nc1
Temperature: -4 °C
Reaction time: 1.25 h

Procedure:
A suspension of 12.62 g of p-(5-butyl-2-pyrimidinyl)-benzoic acid in 150 ml of acetone was treated dropwise with a solution of 8.1 ml of triethylamine in 25 ml of acetone while cooling with an ice/sodium chloride bath (internal temperature -4° C.) and thereafter dropwise within 15 minutes with a solution of 4.9 ml of methyl chloroformate in 25 ml of acetone. The suspension was stirred for a further 75 minutes and then treated dropwise within 10 minutes with a solution of 4.90 g of sodium azide in 17.5 ml of water. The mixture was stirred for another 1 hour while cooling with the ice/sodium chloride bath and then for 30 minutes without cooling. The mixture was poured on to 300 ml of ice-water and extracted once with 250 ml of diethyl ether and twice with 100 ml of diethyl ether each time. The extracts were washed with 100 ml of water, dried and concentrated in vacuo at a bath temperature of 35° C., whereby 13.32 g of solid, yellowish p-(5-butyl 2-pyrimidinyl)benzoic acid azide were obtained. The azide was dissolved in 100 ml of toluene and the solution was added dropwise slowly to a flask heated to 90° C., whereby a strong evolution of nitrogen took place. The solution was heated to 108° C. for a further 1.5 hours and then concentrated. There were obtained 11.59 g of crude, pale yellow p-(5-butyl-2-pyrimidinyl)phenyl isocyanate; m.p. 48° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C@H:45]2[O:47][CH2:46]2)=[CH:39][C:38]=1[N:48]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[S:49]([CH3:52])(=[O:51])=[O:50])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[F:28][C:2]([F:27])([F:1])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:46][C@H:45]([OH:47])[CH2:44][O:43][C:40]3[CH:41]=[CH:42][C:37]([O:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:38]([N:48]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[S:49]([CH3:52])(=[O:50])=[O:51])[CH:39]=3)[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: O=S(=O)(Oc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1)S(C)(=O)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N(c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CC2)ccc1OCc1ccccc1)S(C)(=O)=O

Procedure:
A mixture of 5.52 g of trans-4-[4-(benzylamino)cyclohexyl]phenyl trifluoromethanesulfonate (13.3 mmol) and of 5 g of 4-benzyloxy-3-(N-(tert-butoxycarbonyl)-N-(methylsulfonyl)amino)-1-((2S)-2,3-epoxypropoxy)benzene (11.2 mmol) in ethanol (72 ml) is brought to reflux for 5 h. The solvent is evaporated under reduced pressure and trans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(tert-butoxycarbonyl)(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenyl trifluoromethanesulfonate is obtained in the form of an oil (6.94 g, 72%) after purification on silica gel (eluent: dichloromethane/methanol 98/2). [M+H+]=863.4
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH2:8]([C:15]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[NH:17][N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(OC)C=CC=CC=1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[OH:47][C:41]([C:43]([F:46])([F:45])[F:44])=[O:42].[CH2:8]([C:15]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[NH:17][N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cc3ccccc3)n[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: c1ccc(Cc2cc(C3CCNCC3)[nH]n2)cc1

Procedure:
To a solution of 4-(3-benzyl-(1H-pyrazol-5-yl))-1-(t-butoxycarbonyl)piperidine TFA salt (from Step A) in methylene chloride (1.5 mL) was added anisole (0.017 mL) and TFA (0.230 mL). After several h at rt, volatiles were removed under reduced pressure. Purification of the residue was done by preparative reverse-phase HPLC using a 9.4×250 mm Semi-preparative Zorbax SB-C18 column with a 15-25% acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min at 6.0 mL per minute to give the title compound (40.7 mg) as a gel.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@H:25]4[CH2:30][O:29][C@H:28]([CH2:31][OH:32])[C@@H:27]([OH:33])[CH2:26]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[CH:9][C:8]=2[Cl:34])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:48][C:49]([Si:52](Cl)([CH3:54])[CH3:53])([CH3:51])[CH3:50].C(=O)(O)[O-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl.CO>[C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@H:25]4[CH2:30][O:29][C@H:28]([CH2:31][O:32][Si:52]([C:49]([CH3:51])([CH3:50])[CH3:48])([CH3:54])[CH3:53])[C@@H:27]([OH:33])[CH2:26]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])[C:10]3=[CH:9][C:8]=2[Cl:34])=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@H](CO)[C@@H](O)C2)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC[C@H](Oc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C[C@@H]1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (2R,3S,5R)-5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol (242 mg, 0.416 mmol) in anhydrous DMF (2.0 mL) under nitrogen was added DMAP (10 mg, 0.083 mmol) and triethylamine (0.13 mL, 93 mg, 0.915 mmol). The mixture was cooled to 0° C., then TBSCl (132 mg, 0.873 mmol) was added as a solution in anhydrous DCM (0.5 mL). After stirring at 0° C. for 0.5 hours, methanol (5 mL) was added and the mixture was poured into saturated aqueous sodium bicarbonate (75 mL). The mixture was extracted with ethyl acetate (2×100 mL), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resultant oil was chromatographed using a Biotage™ 10 g silica gel cartridge eluted with 0-20% EtOAc in 1:1 Hexane/DCM over 20 column volumes. The combined product fractions were concentrated under reduced pressure and dried under high vacuum overnight to provide the desired product as a white solid film. LC-MS: calculated for C36H50ClN3O5Si2 695.30, observed m/e: 696.39 (M+H)+ (Rt 3.33/4 min).
Reaction SMILES: C([Si](CC)(CC)[C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][NH2:15])=[CH:10][C:9]([C:16]([F:19])([F:18])[F:17])=[CH:8][CH:7]=2)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:18][C:16]([F:17])([F:19])[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]=[C:12]2[CH2:13][CH2:14][NH2:15]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCN
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NCCc1c[nH]c2ccc(C(F)(F)F)cc12

Procedure:
3.8 g of the compound obtained in Step C are stirred for 72 hours at ambient temperature in 200 ml of tetrahydrofuran and 10 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran in the presence of 1 g of 3 Å molecular sieve. After filtering off the resin and evaporating to dryness, the residue is taken up in 100 ml of 1N HCl and washed with dichloromethane. The aqueous phase is then rendered alkaline and extracted with dichloromethane and the combined organic phases are worked up in customary manner. The product obtained crystallises as the hydrochloride in an ethanol-diethyl ether-hydrogen chloride mixture.
Reaction SMILES: C([O-])(O)=O.[Na+:5].[O-]S([O-])=O.[Na+].[Na+].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>O>[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)(=[O:15])=[O:14].[Na+:5]
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(S(=O)[O-])cc1
Temperature: 80 °C

Procedure:
To a solution of 0.57 g of NaHCO3 (7.1 mmol) and 1.1 g of Na2SO3 (8.8 mmol) in water (5.0 mL) were added 1.0 g (3.9 mmol) of 4-methanesulfonyl-benzenesulfonyl chloride. The reaction was heated at 80° C. for 3 h. The solvent was removed under reduced pressure. The filtrate was concentrated under reduced pressure to give sodium 4-methanesulfonyl-benzenesulfinate.
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([NH:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])=[O:12])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1ccc(Br)cc1
Temperature: 150 °C

Procedure:
A microwave vial containing 4-bromo-benzoic acid ethyl ester (Ig, 4.36 mmol) and N,N-dimethylethylenediamine (2.37 g, 21.38 mmol) was heated under microwave radiation (150° C., 10 min). The volatiles were removed under rotary evaporation and the crude was used in the next step without further purification. Yield: 1.18 g, 100%. LCMS method: 2, RT: 1.93 min; MI: 271-273 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[CH:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.I[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:15]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][Si:22]([C:21]#[C:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[C:11][C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:15][CH:16]=1)([CH3:24])[CH3:25]
Reactant: C#Cc1cc(OC)cc(OC)c1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
Into a 100 ml round bottom flask was placed a mixture of 1.31 g (0.0081 mole) of 3.5-dimethoxyphenylacetylene, 2.25 g (0.0075 mole) of 4-iodophenyl-trimethylsilylacetylene, 0.016 g (0.084 mmole) of CuI, 0.155 g (0.22 mmole) of bis(triphenylphosphine)palladium(II) dichloride in 15 ml of THF and 15 ml of triethylamine. The light brown solution turned to a suspension within a minute. After ˜40 min, the reaction mixture turned to an orange solution with some white ppt. The reaction was followed by TLC. The mixture was stirred at room temperature under nitrogen overnight. TLC showed presence of staring material still. The reaction was stirred continuously overnight at room temp. Not much further reaction had occurred. It was then stirred overnight at 50° C. TLC indicated that only a trace of starting material was present. The reaction was then terminated and the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 15 ml of chloroform and the solution was washed two times with water (15 ml each) and dried over anhydrous MgSO4, filtered and concentrated. 2.27 g (90.4% yield) of solid was obtained. 1HNMR: 0.26 ppm (s, 9H); 3.83 ppm (s, 6H); 6.49 ppm (s, 1H); 6.70 ppm (s, 2H); 7.47 ppm (s, 4H).