Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22]#[N:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2].C(N(CC)CC)C.[SH2:31]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[S:31])[NH2:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2]
Reactant: S
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reaction time: 16 h

Procedure:
A solution of 10-[(2RS)-1-(N-ethyl-N-methyl-amino)-2-propyl]-2-phenothiazinecarbonitrile (3 g) and triethylamine (1.3 cc) in anhydrous pyridine (60 cc) is treated with excess hydrogen sulphide, and stirring is then continued for 16 hours at a temperature in the region of 20° C. The solution obtained is purged with a stream of nitrogen for 1 hour, poured into ethyl acetate (100 cc), washed with distilled water (3×200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at.40° C. The residual brown oil is purified by chromatography on a column (height: 40 cm; diameter: 3 cm) of silica gel (0.2-0.06 mm), eluting successively with methylene chloride (1 liter), a mixture (95:5 by volume) (1 liter) of methylene chloride and methanol and a mixture (80:20 by volume) (3 liters) of methylene chloride and methanol, and collecting 150-cc fractions. Fractions 26 to 30 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[(2RS)-1-(N-Ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbothioamide (2.15 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[N:8]=2
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ncccc2C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ncccc4C(F)(F)F)cc3)C2=N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
A mixture of 5-chloro-3-(4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyridin-2-amine (450 mg) in THF (dry) (10 mL) was added to a mixture of NaH (60%, 246 mg) and 2-chloroethanesulfonyl chloride (602 mg) in THF (dry) (10.0 mL) at room temperature. The mixture was stirred at 70° C. for 3 hr. Water was added and the mixture was concentrated in vacuo. The residue was washed with water and Et2O to give an off-white solid. The solid was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (315 mg) as a white solid. The solid was crystallized from CH3CN-IPE to give a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].[CH3:22][N:23]1[CH:27]=[C:26]([CH2:28][C:29]2[C:30](=[O:36])[NH:31][C:32](=[S:35])[NH:33][CH:34]=2)[CH:25]=[N:24]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:22][N:23]1[CH:27]=[C:26]([CH2:28][C:29]2[C:30](=[O:36])[N:31]=[C:32]([S:35][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[NH:33][CH:34]=2)[CH:25]=[N:24]1
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(C(F)(F)F)cn1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4ccc(C(F)(F)F)cn4)c(C#N)c3)nc2=O)cn1
Temperature: 60 °C
Yield: 42.1 %

Procedure:
To a solution of 5-(chloromethyl)-2-{[5-(trifluoromethyl)-2-pyridinyl]oxy}benzonitrile (97 mg, 0.310 mmol) and 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (76 mg, 0.341 mmol) in chloroform (2 mL) was added dropwise DIPEA (0.163 mL, 0.931 mmol) at 0° C. The mixture was heated at 60° C. for 2 h. Purification via reverse phase flash chromatography then afforded the title compound (65 mg, 42.0% yield). LCMS: rt=2.98 min, [M+H+]=499
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: [N-]=[N+]=Nc1ccc(CBr)cc1

Procedure:
To p-azidotoluene (2.2 mM) prepared as above was added N-bromosuccinimide (2.48 mM), and azo-isobutyronitrile (0.214 mM) in anhydrous benzene (5 ml). This was left to reflux for 5 hours, with the reaction being monitored by TLC. The organics were extracted into diethyl ether (3×15 ml), and water, dried over magnesium sulphate, and the excess solvent removed under vacuum. The p-azidobenzyl bromide formed was isolated using chromatographic techniques.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH:20]1[CH2:26][C:25](=O)[O:24][C:22](=[O:23])[CH2:21]1>ClCCl.Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:25]([CH2:26][CH:20]([C:11]3[CH:12]=[CH:13][C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:10]=3)[CH2:21][C:22]([OH:24])=[O:23])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C1CC(c2ccc3ccccc3c2)CC(=O)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
4-Chloro-1,2-phenylenediamine (143 mg) and 3-(2-naphthyl)glutaric anhydride (240 mg) were dissolved in dichloromethane (3 ml) with heating. The dark solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried in vacuo to give a mixture of regioisomeric amides (0.32 g) as brownish solid. This solid was dissolved in 4M HCl in 1,4-dioxane (4 ml) and the dark solution was heated to reflux for 1 h. After removal of the solvent in vacuo the residue was taken up in acetic acid (5 ml), treated with charcoal, and filtered. From the filtrate the solvent was removed and the residue triturated with acetone to give 4-(5-chloro-2-benzimidazolyl)-3-(2-naphthyl)butanoic acid HCl (138 mg) as colourless solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1.[Cu][C:14]#[N:15]>CC(N(C)C)=O>[CH:11]([C:4]1[CH:3]=[C:2]([C:14]#[N:15])[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=1)=[O:12]
Reactant: O=Cc1cc(Br)c2c(c1)CCO2
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(C=O)cc2c1OCC2
Yield: 61.4 %

Procedure:
To a solution of 7-bromo-2,3-dihydro-1-benzofuran-5-carbaldehyde (1.3 g, 4.7 mmol) in dimethylacetamide (2 mL) was added copper(I) cyanide (0.41 g g, 4.7 mmol). The reaction was refluxed for 18 hours, and then concentrated under reduced pressure. The residue was washed well with warm ethyl acetate. The combined ethyl acetate layer were concentrated and dried. The crude product was purified by flash column chromatography (silica gel, 4:1 and 2:1 hexane:ethyl acetate gradient) to afford the desired product (0.5 g, 50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)[C:5]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:4]=2[O:3]1.[C:23]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][C:2]1([CH3:22])[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]([CH3:23])[C:11](=[O:15])[CH:10]=2)[C:5]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:4]=2[O:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)N=C(Oc2cc[nH]c(=O)c2)c2cc(C#N)ccc2O1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cn1ccc(OC2=NC(C)(C)Oc3ccc(C#N)cc32)cc1=O
Reaction time: 2 h

Procedure:
A mixture of 295 mg of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-2H-1,3-benzoxazine, 20 ml of acetone, 400 mg of K2CO3 and 0.2 ml of dimethyl sulfate is boiled for 2 hours. The mixture is filtered and subjected to customary work-up to give 2,2-dimethyl-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-2H-1,3-benzoxazine.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH3:26][C:27]1[C:31]([CH3:32])=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[O:29][N:28]=1.NC1ON=C(C)C=1C.C(N(C(C)C)CC)(C)C>C(#N)C>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:34]([NH:33][C:30]3[O:29][N:28]=[C:27]([CH3:26])[C:31]=3[CH3:32])=[O:35])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Reactant: Cc1noc(NC(=O)Oc2ccccc2)c1C
Agent: Cc1noc(N)c1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1noc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cc4)c3)CC2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-(4-(Trifluoromethyl)phenoxy)benzylidene)piperidine hydrochloride (200 mg, 0.541 mmol, from Example 53, Step 5), phenyl 3,4-dimethylisoxazol-5-ylcarbamate (126 mg, 0.541 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 5-amino-3,4-dimethylisoxazole) and diisopropylethylamine (0.20 mL, 1.15 mmol) were combined in acetonitrile (5 mL) and stirred at room temperature. After 16 h, the reaction was concentrated and the residue was purified by silica gel chromatography (0-30% EtOAc:CH2Cl2) to afford the title compound (218 mg) as a white solid. MS APCI M+ 472.3, 431.2, 375.3, 334.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.83 (s, 3H) 2.18 (s, 3H) 2.44 (td, J=5.77, 1.07 Hz, 2H) 2.54 (td, J=5.81, 1.16 Hz, 2H) 3.49-3.54 (m, 2H) 3.59-3.63 (m, 2H) 6.44 (s, 1H) 6.90-6.98 (m, 2H) 7.05-7.14 (m, 3H) 7.35-7.44 (m, 1H) 7.59-7.67 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH2:13][N:12]([C:14](=[O:16])[CH3:15])[CH2:11][CH2:10][C:9]=2N2CCCCC2)=O)=[CH:4][CH:3]=1.CCN(CC)CC.Cl.[CH3:33][CH:34]([CH3:38])[C:35](=[NH:37])[NH2:36]>C(O)(CC)(C)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[C:8]3[CH2:13][N:12]([C:14](=[O:16])[CH3:15])[CH2:11][CH2:10][C:9]=3[N:37]=[C:35]([CH:34]([CH3:38])[CH3:33])[N:36]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=N)N
Reactant: CC(=O)N1CCC(N2CCCCC2)=C(C(=O)c2ccc(F)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCC(C)(C)O
Product: CC(=O)N1CCc2nc(C(C)C)nc(-c3ccc(F)cc3)c2C1
Temperature: 25 °C

Procedure:
A solution of crude 1-[5′-(4-fluoro-benzoyl)-3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl]-ethanone in t-amyl alcohol (1.5 L) was treated with Et3N (108 mL, 0.78 mol) and 2-methyl propanimidamide hydrochloride (82.6 g, 0.67 mol). The reaction mixture was heated at reflux for 16 h and then was cooled to rt. The mixture was concentrated, and the residue was diluted with water (2 L) and extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated to afford the crude title compound, which was used in next reaction without further purification. HPLC: RT=8.11 min. MS (ESI): exact mass calcd. for C18H20FN3O, 313.16; m/z found, 314.0 [M+H]+. 1H NMR (CDCl3; mixture of rotamers): 7.60-7.50 (m, 2H), 7.24-7.12 (m, 2H), 4.71 (s, 1.4H), 4.56 (s, 0.6H), 3.93 (t, J=6.2, 0.6H), 3.80 (t, J=6.2, 1.4H), 3.18 (sept, J=6.8, 1H), 3.07 (t, J=6.2, 1.4H), 3.02 (t, J=6.2, 0.6H), 2.15 (s, 2.1H), 2.00 (s, 0.9H), 1.34 (d, J=6.8, 6H).
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:35]=[CH:34][C:9]([C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([O:25]C)=[O:24])[C:17]2=[O:33])=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[OH-:36].[Na+]>CO.O>[C:23]([CH:22]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:18][C:17](=[O:33])[N:16]([CH2:20][C:19]([OH:36])=[O:21])[CH2:15][CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]1[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:35][CH:34]=1)([OH:25])=[O:24]
Reactant: COC(=O)C(c1ccccc1)N1C(=O)CN(CCCNC(=O)c2ccc(NC(=N)N)cc2)C1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(N)Nc1ccc(C(=O)NCCCN(CC(=O)O)C(=O)NC(C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
380 mg (0.76 mg) of methyl (3-(3-(4-guanidinobenzoylamino)propyl)-2,5-dioxoimidazolidin-1-yl)phenylacetate hydrochloride are dissolved in 10 ml of methanol and 10 ml of water, and 2.28 ml of 1N sodium hydroxide solution are then added. The mixture is stirred at room temperature overnight, concentrated and chromatographed, for purification, on Sephadex LH20 using an homogeneous mixture of butanol/glacial acetic acid/water.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[C@@H:27]([F:32])[CH2:26]1)[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:31][C@@H:28]4[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][C@@H:27]4[F:32])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN1CC[C@@H](N)[C@@H](F)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCN1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)[C@@H](F)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.35 g, 45.5 mmol), (3S,4R)-1-ethyl-3-fluoro-piperidin-4-ylamine (dihydrochloride salt) (6.30 g, 29.0 mmol), diisopropylethylamine (21.0 ml, 120 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 14 h. The mixture was cooled to 25° C. and was stirred at that temperature for 4 h. The resulting yellow precipitate was collected by vacuum filtration, washed with Et2O (1×30 ml), and air-dried to give (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-((3S,4R)-1-ethyl-3-fluoro-piperidin-4-yl)-amine (11.5 g, 90% over 3 steps) as a yellow solid. LCMS (Method G, ESI): RT=0.69 min, m+H=448.3; 1H NMR (400 MHz, CDCl3) δ 9.35 (d, J=8.4 Hz, 1H), 9.12 (s, 1H), 8.29-8.11 (m, 2H), 7.69-7.59 (m, 2H), 7.52 (t, J=7.8 Hz, 2H), 7.26 (s, 1H), 6.65 (d, J=4.2 Hz, 1H), 4.86 (d, J=48.6 Hz, 1H), 4.28-4.05 (m, 1H), 3.27-3.13 (m, 1H), 2.97-2.87 (m, 1H), 2.52 (q, J=7.2 Hz, 2H), 2.49-2.37 (m, 1H), 2.29 (t, J=10.0 Hz, 1H), 2.15-1.98 (m, 2H), 1.12 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([CH3:9])([SH:8])[CH3:7])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[C:20]=1[CH2:21]O>C(Cl)Cl>[NH2:1][C@H:2]([C:6]([CH3:9])([S:8][CH2:21][C:20]1[C:23]([O:29][CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=1[O:18][CH3:17])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: COc1cc(OC)c(CO)c(OC)c1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(CSC(C)(C)[C@@H](N)C(=O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A suspension of (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid (5.0 g, 703 mmol) in CH2Cl2 (150 mL) was cooled to 0° C. Trifluoroacetic acid (54 mL, 703 mmol) was added dropwise over a period of 5 min. 2,4,6-trimethoxybenzyl alcohol (6.64 g, 34 mmol) in CH2Cl2 (137 mL) was added dropwise at 0° C. with stirring. The stirring was continued for 1 hour at 0° C. and 2 hours at room temperature, the solvent removed in vaciio and the residue was dried under high vacuum for 3 hours. The crude red solid was recrystallized from 1:1:1 CH2Cl2:MeOH:EtOAc to give the title compound 10.5 g (95 %) as a white solid which was used for the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 6.10 (s, 2H), 3.84 (s, 6H), 3.76 (s, 3H), 3.40-4.10 (mult, 3H), 1.69 (s, 3H), 1.23 (s, 3H); mass spectrum (API-TIS) m/z 330 (M+H).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Br:7][C:8]1[C:9]([Cl:15])=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(#N)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:5]#[N:6])=[N:10][C:9]=1[Cl:15]
Reactant: [O-][n+]1cccc(Br)c1Cl
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Br)c(Cl)n1
Temperature: 50 °C

Procedure:
Trimethylsilyl cyanide (19 mL, 0.15 mol) was added to a stirred solution of 3-bromo-2-chloropyridine 1-oxide (C27) (31.6 g, 0.152 mol) and triethylamine (63.4 mL, 0.46 mol) in acetonitrile (400 mL). The reaction mixture was heated to 50° C. for 2 hours. It was then cooled to room temperature and additional trimethylsilyl cyanide (19 mL, 0.15 mol) was added. After the reaction mixture was heated at 50° C. for 1.5 hours, a final portion of trimethylsilyl cyanide (28.5 mL, 0.23 mol) was added and the reaction was heated at reflux for 3 days. After dilution with dichloromethane (2 L), the reaction was washed with saturated aqueous sodium bicarbonate solution (800 mL), then with water (1 L), dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 20% to 25% ethyl acetate in heptane) afforded the title compound as a yellow solid. Yield: 14.92 g, 68.6 mmol, 45%.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C(=O)(O)[O-:28].[Na+].I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[Si:1]([O:8][CH:9]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc2ccccc2c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)[Si](C)(C)OC(CCCCC=O)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of alkene 182 (1.05 g, 3.23 mmol) in t-butyl alcohol (50 mL) were successively added water (10 mL), solid sodium bicarbonate (2.71 g, 32.3 mmol), sodium periodate (4.15 g, 19.38 mmol), and osmium tetroxide (8 mg, 0.032 mmol). The mixture turned light brown and a precipitate formed in large amount, making magnetic stirring impossible so the mixture was shaken by hand every 10 minutes for 3.5 hours and the brownish color almost disappeared. The reaction was quenched with a 10% aqueous solution of sodium thiosulfate. After 30 minutes, the white precipitate was filtered off and rinsed with diethyl ether. The filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether and water. The aqueous layer was extracted (2×50 mL) with diethyl ether. The combined organic layers were washed successively with a 10% aqueous solution of sodium thiosulfate, water and brine, dried (MgSO4), and concentrated in vacuo, yielding the title compound 183 as a crude oil in 91% yield (1.05 g). 1H NMR: (300 MHz, CDCl3) δ: 9.73 (t, J=1.9 Hz, 1H), 7.83-7.78 (m, 3H), 7.69 (s, 1H), 7.49-7.43 (m, 3H), 4.80 (t, J=6.9 Hz, 1H), 2.39 (td, J=7.1, 1.6 Hz, 2H), 1.81-1.55 (m, 4H), 1.43-1.25 (m, 2H) 0.90 (s, 9H), 0.04 (s, 3H), −0.15 (s, 3H). MS (ESI) 225 (M+1-TBSO).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([S:23](Cl)(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([S:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CCN(CC1CCN(S(=O)(=O)Cl)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CC1CCN(S(=O)(=O)N2CCOCC2)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-chlorosulfonylpiperidin-4-ylmethyl)amine (0.18 grams, 0.45 mmole), morpholine (0.04 grams, 0.45 mmol) and diisopropylethylamine (0.12 grams, 0.93 mmole) in tetrahydrofuran (10 ml) was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was dried over potassium carbonate and evaporated to give a residue, which was purified by flash chromatography on silica gel using 40% ethyl acetate in hexane. Appropriate fractions were combined and evaporated to give (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-[1-(morpholine-4-sulfonyl)-piperidin-4-ylmethyl]amine as an oil, (0.17 g, 85%), M+H 452. Analysis % of the hydrochloride salt: Found: C, 54.06; H, 7.62; N, 8.24. Requires: C, 54.01; H, 8.00; N, 8.22.
Reaction SMILES: [OH:1][CH:2]([CH:19]([CH3:21])[CH3:20])[C:3]([CH3:18])([CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9].[C:22](Cl)(=[O:24])[CH3:23]>>[C:22]([O:1][CH:2]([CH:19]([CH3:21])[CH3:20])[C:3]([CH3:17])([CH3:18])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])(=[O:24])[CH3:23]
Reactant: CC(C)C(O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(=O)Cl
Product: CC(=O)OC(C(C)C)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 50 %

Procedure:
Prepared as in Example 231c from 2-(3-hydroxy-2,2,4-trimethylpentyloxy)-6-nitrobenzonitrile (Example 243d) and acetyl chloride in 50% yield. MS 335 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[O:7]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:28]3[C:27]([NH2:29])=[N:26][CH:25]=[N:24][C:23]=3[NH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O>N1C=CC=CC=1>[C:1]([N:22]1[C:23]2[N:24]=[CH:25][N:26]=[C:27]([NH2:29])[C:28]=2[C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:19][CH:18]=2)=[CH:21]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)C(=O)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Temperature: 20 °C

Procedure:
Isobutyryl chloride (1.8 g) was added dropwise to a mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (4.32 g), dry dimethyl-formamide (200 ml) and dry pyridine (2 ml) with stirring under nitrogen at 20° C. The mixture was stirred at ambient temperature for 1 hour and evaporated under vacuum. The residue was partitioned between water and ethyl acetate. The ethyl acetate was separated, dried and evaporated and the residue obtained was recrystallised from toluene to give 7-isobutyryl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 160.5-161° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#C)[C:5]2[O:9][C:8]([CH2:10][C:11]3[CH:16]=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)=[N:7][C:6]=2[CH:26]=1.BrC1[S:31][CH:32]=[CH:33][N:34]=1>C(N(CC)CC)C.[Pd](Cl)Cl.[Cu]I>[S:31]1[CH:32]=[CH:33][N:34]=[C:16]1[C:11]#[C:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][CH:2]=[CH:26][C:6]=2[N:7]=1
Reactant: C#Cc1cc(Cl)cc2nc(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc12
Reactant: Brc1nccs1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#Cc1nccs1)c1nc2ccccc2o1
Yield: 210.7 %

Procedure:
A suspension of 5-chloro-2-(3,5-di-t-butyl-4-hydroxy-benzyl)-7-ethynyl-benzoxazole (2.38 g, 6.0 mmol), 2-bromothiazole (1.13 ml, 95%, 12 mmol), bistriphenylphosphine)palladium(II) dichloride (21.1 mg, 30 μmol), and copper (I) iodide (1.2 mg, 6 μmol) in triethylamine (12 ml) was heated at 90 EC, under argon, for 3 hours. The triethylamine was removed in-vacuo and the residue dissolved in ether (70 ml) and water (30 ml). The organics were washed with 1 N HCl (30 ml) and saturated sodium hydrogen carbonate (30 ml), dried (Na2SO4) and evaporated--to give 2.86 g (100%) of crude thiazolylethynylbenzoxazole, which was purified by flash chromatography (SiO2 ; dichloromethane). The product was crystallized and recrystallized from methanol to give 1.43 g (50.4%) of the title compound (mp 137-41 EC).