Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C1COCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][C:30]([C:2]2[CH:14]=[CH:13][C:5]([O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)=[CH:4][CH:3]=2)([OH:33])[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(OC3CCCCO3)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A solution of 2-(4-bromophenoxy)-tetrahydropyran (7.2 g, 28 mmol) in THF (70 ml) was cooled to −60° C., to which n-butyl lithium (1.53 M) hexane solution (20 ml, 30.8 mmol) was added dropwise, and the mixture was stirred for 30 minutes. Then, a solution of 1-benzyl-4-piperidone (5.3 g, 28 mmol) in THF (20 ml) was added dropwise to this mixture, which was stirred for 3 hours while being allowed to reach a temperature of 0° C. Saturated ammonium chloride aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to afford 1-benzyl-4-[4-(tetrahydropyran-2-yloxy)phenyl]piperidin-4-ol (5.27 g, yield 51%) as an orange-colored oil.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[NH:5][C:4](=[O:12])[N:3]=1.[CH3:13][Si:14]([CH3:21])([CH3:20])[NH:15][Si](C)(C)C>>[CH3:13][Si:14]([NH:15][N:5]1[C:6]2[C:11](=[N:10][CH:9]=[CH:8][N:7]=2)[CH:2]=[N:3][CH:4]1[O:12][Si:14]([CH3:21])([CH3:20])[CH3:13])([CH3:21])[CH3:20]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Nc1nc(=O)[nH]c2nccnc12
Product: C[Si](C)(C)NN1c2nccnc2C=NC1O[Si](C)(C)C

Procedure:
To 20 mL of hexamethyldisilazane (HMDS) is added 2.98 g (0.02 mole) of 4-amino-pteridine-2-one (30). The mixture is heated for 24 hours under reflux, with moisture excluded, to obtain a clear solution. The excess HMDS is removed under high vacuum to give 1-trimethylsilylamino-2-trimethylsilyloxy-pteridine as a viscous oil. The residue is dissolved in 200 mL of benzene and then 9.37 g (0.022 mole) of 2-deoxy-3,5- di-O-toluoyl-α-D-ribofuranosyl chloride, 4 g HgO, and 4 g HgBr2 are added and the mixture is refluxed for 5 hours. After cooling, the precipitate is filtered off, the flitrate evaporated to dryness and the residue dissolved in 100 mL of CHCl3. The solution is extracted twice with 100 mL of 20% KI. The organic layer is then dried over Na2SO4, again evaporated and the residue dissolved in a little ethyl acetate for silica-gel column chromatography with ethyl acetate/acetone 7:3. The first fraction contains excess sugar, the second fraction the α-anomer and last eluting fraction the β-deoxyriboside. Evaporation and recrystallization of the residue from ethanol gives 31.
Reaction SMILES: [CH3:1][Si](N([Li])[Si](C)(C)C)(C)C.[Cl:11][C:12]1[N:17]=[C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][C:21](=O)[CH2:20]2)[C:15]([F:26])=[CH:14][N:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:11][C:12]1[N:17]=[C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][C:21](=[CH2:1])[CH2:20]2)[C:15]([F:26])=[CH:14][N:13]=1
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (0.86 g, 2.40 mmol) in THF (100 mL) in a flamed dry flask was added (bis(trimethylsilyl)amino)lithium (2.40 mL of 1 M solution, 2.40 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 1 hr. A solution of (S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanone, 29b, (0.48 g, 2.00 mmol) in 20 mL of THF was added. The reaction was allowed to stir at room temperature for 2 hrs. The mixture was quenched by pouring into brine and the aqueous phase was extracted with EtOAc. The layers were separated and the organic was dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford 270 mg of the desired product: LCMS RT: 3.83 min, (M+1): 242.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](OC)=[O:14])=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:2]1
Reactant: COC(=O)CCCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
A tetrahydroturan solution (500 ml) of methyl 4-(3-indolyl)-butyrate (103 g) was added dropwise to a suspension of lithium aluminium hydride (25 g) in tetrahydrofuran (1000 ml) at 40° C. followed by stirring for 1 h at room temperature. Usual work-up gave 4-(3-indolyl)-1-butanol (96 g) as an oil. Arylation with 1-fluoro-4-iodobenzene according to the method described in EXAMPLE 5 yielded 4-[1-[4-fluorophenyl)-3-indolyl]-1-butanol which was converted to the title compound 9a by the method described in EXAMPLE 2 using spiro[1H-2-benzopyran-4(3H),4'-piperidine]. The maleate salt crystallized from acetone by addition of maleic acid. Yield: 1.5 g, mp: 189°-90° C.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([C:13]([CH3:32])([CH3:31])[CH2:14][C:15]([CH2:21][C:22]2[NH:30][C:25]3=[CH:26][N:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:11][CH:12]=1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[F:19][C:16]([F:17])([F:18])[C:15]([OH:20])([CH2:21][C:22]1[NH:30][C:25]2=[CH:26][N:27]=[CH:28][CH:29]=[C:24]2[CH:23]=1)[CH2:14][C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH:2]=[O:1])([CH3:31])[CH3:32]
Reactant: CC(C)(CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F)c1cccc(C2OCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: CC(C)(CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.3 %

Procedure:
A mixture of 4-(3-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol (160 mg, 0.36 mmol), 2 mL of ethanol, 1 mL of water, and pyridinium p-toluenesulfonic acid (200 mg, 0.8 mmol) was stirred at room temperature for 14 hours and then concentrated in vacuo to remove ethanol. The residue was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with aqueous saturated sodium bicarbonate solution and brine, and dried over sodium sulfate. Removal of the solvent in vacuo afforded 134 mg (95% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)[CH2:2][CH3:3].[F:13][C:14]1[CH:25]=[C:24]2[C:17]([NH:18][CH:19]=[C:20]2[CH2:21][CH2:22][NH2:23])=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.COCCOCCOC>[F:13][C:14]1[CH:25]=[C:24]2[C:17](=[CH:16][CH:15]=1)[NH:18][CH:19]=[C:20]2[CH2:21][CH2:22][NH:23][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: CCCOc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CO
Product: CCCOc1cccc(CNCCc2c[nH]c3ccc(F)cc23)c1

Procedure:
Combine 3-propoxybenzaldehyde (29.6 mg; 0.18 mmol) and 5-fluorotryptamine (14.2 mg; 0.080 mmol) in methanol (2 mL). Add a solution of sodium borohydride in diglyme (1 ml of a 0.5 M solution; 0.50 mmol)and agitate. After 63 h at room temperature concentrate in a stream of nitrogen. Dissolve the residue in methanol and add to a 1 gm SCX column previously rinsed with 5% acetic acid in methanol. Elute the product from the SCX column with 1 M ammonia in methanol to give the title compound: MS (ES+): m/e (M+1); HPLC (10–90% water/acetonitrile over 10 min, Tr=4.08 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:15]=1[C:16](Cl)=[O:17]>C(#N)C.CC(C)=O>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:15]=1[C:16]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12])=[O:17]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Solvent: CC(C)=O
Solvent: CC#N
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1c(F)c(F)c(F)c(F)c1F
Yield: 84.9 %

Procedure:
In 100 ml of acetonitrile was dispersed 18.9 g (0.10 mole) of 2-amino-4-chloro-5-nitrophenol and a solution of 23.1 g (0.10 mole) of 2,3,4,5,6-pentafluorobenzoyl chloride in 50 ml of acetone was added dropwide to the resultant dispersion. After heating under reflux for 3 hours, the reaction mixture was ice-cooled and the precipitated solids were collected by filtration, washed with cooled acetonitrile and dried to obtain 32.5 g of 2-(2,3,4,5,6-pentafluorobenzamido)-4-chloro-5-nitrophenol (Yield 85%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:23]([C:34]([O:36][CH3:37])=[O:35])[CH2:22]1.[N:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1.O1CCCC1.N(C(OCC)=O)=NC(OCC)=O>>[N:38]1[CH:43]=[CH:42][C:41]([O:20][C@@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C@@H:23]([C:34]([O:36][CH3:37])=[O:35])[CH2:22]2)=[CH:40][CH:39]=1
Reactant: COC(=O)[C@H]1C[C@@H](O)CC[C@@H]1C(=O)OC(C)(C)C
Reactant: Oc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2ccncc2)CC[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (2.0E3 mg, 0.0077 mol) was added To a solution of 1-tert-butyl 2-methyl(1S,2S,4S)-4-hydroxycyclohexane-1,2-dicarboxylate (1.0 g, 0.0039 mol) and 4-pyridinol (730 mg, 0.0076 mol) in tetrahydrofuran (10.0 mL, 0.123 mol) at rt. A solution of diethyl azodicarboxylate (1200 uL, 0.0077 mol) in tetrahydrofuran (10.0 mL, 0.123 mol) was added. The reaction mixture was stirred at rt overnight. The reaction was chromatographed by combiflash (ethyl acetate in hexanes: 80%) to give 1-tert-butyl 2-methyl(1S,2S,4R)-4-(pyridin-4-yloxy)cyclohexane-1,2-dicarboxylate, contaminated with a little Ph3PO, which was used in next step.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CN=C1.[C:10]([Si:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)Cl)([CH3:13])([CH3:12])[CH3:11].[Cl-].[Na+]>CN(C)C=O>[Br:1][CH2:2][CH2:3][O:4][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCBr
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
Separately, 2.50 g (corresponding to 20.0 mmol) of 2-bromoethanol and 2.72 g (corresponding to 40.0 mmol) of imidazole were dissolved in 10 mL of dimethylformamide (DMF), and cooled to 0° C. Then, 5.50 g (corresponding to 20.0 mmol) of t-butyldiphenylchlorosilane (TBDPSC1) was added thereto. After the reaction mixture was stirred at room temperature for 18 hours, a saturated sodium chloride solution was added, and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1) to obtain 7.04 g (corresponding to 19.4 mmol) of 1-bromo-2-(t-butyldiphenylsiloxy)ethane (FIG. 2-1, Step 3).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[C:7]([O:14]C)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S].[NH:17]1[CH2:22]COC[CH2:18]1>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:17]([CH3:22])[CH3:18])=[C:7]([OH:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)(C)C)ccc1C(C)=O
Reactant: C1COCCN1
Agent: [S]
Solvent: O
Product: CN(C)CCc1ccc(C(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.76 g (27.9 mmol) of 1-(4-tert-butyl-2-methoxyphenyl)ethanone (described in patent applications WO 01/02366; WO 99/52857; WO 99/21836; WO 97/48683), 1.1 g (34.3 mmol) sulfur and 15 mL morpholine (0.172 mol) was refluxed overnight under a nitrogen atmosphere. The reaction mixture was cooled and poured into 200 mL water containing 30 g sodium hydroxide and the resulting mixture was again refluxed overnight. The reaction mixture was then cooled to room temperature, diluted with an equal volume of water, and filtered through a pad of Celite filter aid. The filtrate was then cooled with an external ice water bath and acidified. The resulting precipitate was filtered, washed with water and air dried. The residue was then suspended in EtOAc and filtered to remove insoluble material and the filtrate was concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:15]O.O>C(O)(=O)C>[CH:1]1[C:14]2[S:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Oc1ccccc1S2
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: O=S1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 168 h
Yield: 83 %

Procedure:
100 g (0.5 mole) of phenoxathiin was dissolved in 1,600 g of acetic acid, after which 48.5 g (0.5 mole) of 35% hydrogen peroxide was added dropwise to the solution. The solution was further stirred for seven days at room temperature. Then, 3,000 g of water was added to the reaction solution to settle out white crystals. The crystals were collected by filtration and dried in vacuum, obtaining the target compound. White crystals, 90 g (yield 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:21][C:20]2[C:19]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[C:20]4[S:21][C:13]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[CH:14][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from p-methoxybenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H),11.2 (s, 1H), 8.81 (s, 1H), 7.55 (m, 6H), 7.20 (d, 1H). 7.05 (m, 2H), 6.50 (s, 1H), 3.79 (s, 3H). M.P. 150-180° C.; LC-MS: 373 (MH+); HPLC RT: 4.45 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]1.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[CH:33]1([CH2:32][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=2[CH:10]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]2)[CH2:31][CH2:30]1
Reactant: COc1cccc(O)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: BrCC1CC1
Product: COc1cccc(OCC2CC2)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2-hydroxy-6-methoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-one with commercially available (bromomethyl)cyclopropane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.86 min.; [M+H]+: 449.76 g/mol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]#[N:21])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[OH:22][C@H:23]([CH3:27])[C:24](O)=[O:25].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[C:20]([CH2:19][CH2:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([NH:11][C:3]2[C:2]([NH:1][C:24](=[O:25])[C@H:23]([OH:22])[CH3:27])=[CH:7][N:6]=[C:5]3[CH:8]=[CH:9][S:10][C:4]=23)[CH2:17][CH2:16]1)#[N:21]
Reactant: N#CCC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CCC#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-{trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}propanenitrile (0.048 g, 0.16 mmol) and (R)-2-hydroxypropanoic acid (0.019 g, 0.21 mmol) in methylene chloride (0.96 mL) was added N,N-diisopropylethylamine (60 μL, 0.35 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (66 mg, 0.17 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was washed with water. The organic layers were concentrated and purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give (2R)—N-(7-{[trans-4-(2-Cyanoethyl)cyclohexyl]amino}thieno[3,2-b]pyridin-6-yl)-2-hydroxypropanamide. LCMS calculated for C19H25N4O2S (M+H)+: m/z=373.2. Found: 373.0. A solution of the amide intermediate in acetic acid (0.3 mL) was stirred at 105° C. for 5 h. The solvent in the reaction mixture was removed in vacuo, diluted with MeOH and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (6 mg, 10%). LCMS calculated for C19H23N4OS (M+H)+: m/z=355.2. Found: 355.1.
Reaction SMILES: [Li+].[Cl-].C(COC)OC.Br[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([Mg]Cl)=[CH:20][CH:19]=1>O1CCCC1>[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:20][CH:19]=1
Reactant: Cc1ccc([Mg]Cl)cc1
Reactant: N#Cc1ccccc1Br
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of MnCl2 (0.25 g, 1.98 mmol) and LiCl (0.17 g, 3.955 mmol) in a mixture of 2 ml of anhydrous tetrahydrofuran and 0.38 ml of dimethoxyethane (3.955 mol) is stirred at room temperature until, after approximately 30 minutes, a homogeneous medium is obtained. The PdCl2/dppp complex (0.0023 g, 0.1 mol %) and the o-bromobenzonitrile (0.72 g, 3 955 mmol) are then added and then a solution of p-tolylmagnesium chloride in tetrahydrofuran (1.80N, 2.86 ml, 5.14 mmol) is added over 30 minutes. After stirring for 30 minutes, the reaction mixture is treated as described in Example 4. The o-(p-tolyl)benzonitrile is thus obtained with a yield of isolated product of 95%.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][C:22](O)([CH3:24])[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([O:19][C:18](=[O:20])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([CH3:24])([CH3:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (S)-N-Boc-4-fluorophenylalanine (2.83 g, 10.0 mmol), DMAP (0.12 g, 1.0 mmol) in DCM (20 mL) and 2-methyl-2-propanol (1.05 mL, 11.0 mmol), was added DCC (2.27 g, 11.0 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered and washed several times with DCM. The filtrate was concentrated in vacuo and chromatographed on silica gel eluting with ethyl acetate:isohexane (1:4) to give the title compound. δH (CDCl3): 1.39 (9H, s), 1.41 (9H, s), 3.01 (2H, m), 4.41 (1H, m), 4.98 (1H, m), 6.95 (2H, m), 7.12 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([Si:13]([CH3:19])([CH3:18])[O:14][CH2:15][C:16]#[CH:17])([CH3:12])([CH3:11])[CH3:10]>[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:17]#[C:16][CH2:15][O:14][Si:13]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:18])[CH3:19])=[CH:4][N:3]=1
Reactant: Nc1cnc(Br)cn1
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)OCC#Cc1cnc(N)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
2-Amino-5-bromopyrazine (1.50 g, 8.6 mmol) was dissolved in anhydrous, deoxygenated DMF (24.5 mL) with triethylamine (10.5 mL). Copper(I) iodide (0.33 g, 1.7 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.61 g, 0.51 mmol) and tert-butyldimethyl(prop-2-ynyloxy)silane (1.90 g, 11.2 mmol) were added and the solution was stirred overnight at 60° C., then cooled and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried (Na2SO4) and evaporated. The residue was purified by silica chromatography to give 2-amino-5-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)pyrazine (2.06 g, 91%) as a brown solid.
Reaction SMILES: [Br-].[NH2:2][C:3]1[N:4]([CH2:20][C:21](=[O:27])[C:22]2[S:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[N+:7]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O.[C:29](OC(=O)C)(=O)[CH3:30]>>[CH3:29][C:30]1[N:2]=[C:3]2[N:4]([C:20]=1[C:21](=[O:27])[C:22]1[S:26][CH:25]=[CH:24][CH:23]=1)[C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[N:7]2[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1n(CC(=O)c2cccs2)c2ccccc2[n+]1CCN1CCCCC1
Agent: [Br-]
Solvent: O
Product: Cc1nc2n(CCN3CCCCC3)c3ccccc3n2c1C(=O)c1cccs1

Procedure:
The bromide obtained in Step A is heated at reflux in 15 ml of acetic anhydride until completely dissolved. Cool and pour into 50 ml of cold water. Neutralise with a solution of sodium carbonate and extract twice with 10 ml of chloroform each time. Combine the organic phases, pass over a column of alumina and evaporate. Recrystallise the residue from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:15][CH2:16][CH3:17].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[O:13][CH2:15][CH2:16][CH3:17]
Reactant: CCCBr
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Product: CCCOc1cc(OC)ccc1C(=O)OC

Procedure:
A stirred mixture of methyl 4-methoxysalicylate (25 g), bromopropane (15.6 ml), potassium iodide (2.82 g) and anhydrous potassium carbonate (27.53 g) was heated under reflux for 48 hours. The cooled reaction mixture was filtered and the filtrate was evaporated under reduced pressure to yield an oil which was dissolved in diethyl ether (200 ml). The ethereal solution was extracted with aqueous sodium hydroxide to remove unreacted starting material and the organic phase was then washed with water and brine, dried (magnesium sulphate) and evaporated under reduced pressure to yield methyl4-methoxy-2-propoxy-benzoate, 22.45 g.