Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: COc1cccc(Cl)n1
Product: COc1cccc(-c2cc([N+](=O)[O-])ccc2F)n1

Procedure:
2-Chloro-6-methoxypyridine (1.26 g, 8.81 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3 g, 11.45 mmol) using the method in Example 47. Purification by chromatography on silica gel eluting with dichloromethane containing 20% isohexane then recrystallisation from toluene/isohexane gave 2-(2-fluoro-5-nitrophenyl)-6-methoxypyridine as a white solid: δH (400 MHz, CDCl3) 4.05 (3H, s), 6.81 (1H, d, J 8), 7.30 (1H, dd, J 10 and 9), 7.48-7.51 (1H, m), 7.69 (1H, t, J 8), 8.22-8.26 (1H, m), 9.08 (1H, dd, J 7 and 3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:24]3[C:23]([C:25](O)=[O:26])=[CH:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1>CN(C=O)C>[O:26]=[C:25]1[C:23]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:18][CH:17]=[C:16]([C:24]=23)[CH2:15][N:14]1[CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2c[nH]c3nccc(C(=O)O)c23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3c[nH]c4nccc(c34)C2=O)CC1
Yield: 54.3 %

Procedure:
3-((1-(tert-Butoxycarbonyl)piperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (35 mg, 0.093 mmol), HATU (71 mg, 0.187 mmol), and pyridine (0.023 mL, 0.280 mmol) were stirred in DMF (3 mL) at room temperature for 2 h. The solution was concentrated in vacuo and purified via basic prep HPLC eluting with 10% to 35% B in A and gave 18 mg of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.59 (m, 1H), 7.39-7.49 (m, 1H), 4.98 (d, 2H, J=1.5 Hz), 4.77-4.79 (m, 1H), 4.25-4.28 (m, 2H), 2.87-2.92 (m, 2H), 1.91-1.94 (m, 2H), 1.78-1.90 (m, 2H), 1.48 (s, 9H). [M+H] found 357.
Reaction SMILES: [Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:21])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([N:14]3C#N)[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:21])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([NH:14]3)[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1
Reactant: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2
Yield: 10.9 %

Procedure:
The nitrile (6.41 g) was dissolved in 300 ml of tetrahydrofuran and, 4.06 g lithium aluminum hydride was added, with stirring. The suspension was heated at reflux for 2 hr and ethyl acetate, water, aqueous sodium hydroxide solution and water were added. The suspension was filtered and the filtrate was concentrated. The residue was triturated with ether and the solid was recrystallized from methanol to give 0.64 g (18%) of the product, mp 260°-263° C. (dec.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[OH:23])(=[O:4])[CH2:2][CH3:3].[CH3:24][C:25](C)([O-:27])C.[K+].BrCCO>COCCOCCOC>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][OH:27])(=[O:4])[CH2:2][CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: OCCBr
Agent: [K+]
Solvent: COCCOCCOC
Product: CCC(=O)c1cnc2c(OCCO)cccc2c1Nc1ccccc1C
Reaction time: 2 h
Yield: 13.7 %

Procedure:
A solution of 3-propanoyl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.06 g, 10 mmol) and potassium t-butoxide (1.68 g, 15 mmol) in diglyme (50 ml) was heated to 150°, a solution of 2-bromoethanol (0.85 ml, 12 mmol) in diglyme (25 ml) added dropwise, then the mixture raised to reflux temperature with vigorous stirring. After 1 hour a further portion of 2-bromoethanol (0.85 ml) was added, and reflux continued for 2 hours. The diglyme was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, ethyl acetate/2% acetic acid/2-5% methanol) and recrystallisation from aqueous isobutyl alcohol gave 3-propanoyl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline (0.48 g), m.p. 174°-176°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](=[N:11][NH2:12])[NH2:10])=[N:6][C:7]=1[CH3:8].[CH:13](O)=O>>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([C:9]2[N:10]=[CH:13][NH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(C(N)=NN)ccc1Br
Reactant: O=CO
Product: Cc1nc(-c2nc[nH]n2)ccc1Br
Temperature: 100 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A 500-mL, three-neck, round-bottom flask was equipped with a mechanical stirrer, a thermocouple connected to a J-KEM temperature controller and a reflux condenser. The flask was charged with 5-bromo-6-methylpicolinohydrazonamide (100 g, 0.463 mol) and formic acid (250 mL). The resulting solution was heated to 100° C. and stirred for 48 h. Formic acid was removed under reduced pressure and the resulting slurry was treated with water (1.5 L) while vigorously stirring. The mixture was filtered and washed with water (300 mL). The solids were transferred into a round-bottom flask and treated with water (1 L) and 1 M sodium hydroxide solution until pH 7. The mixture was allowed to stir for 30 min, filtered, washed with water (300 mL) and dried in a vacuum oven at 30-35° C. for 48 h to afford the product (96 g, 92% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[CH2:10][CH2:9][C:8]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:7][C:6]=2[CH:24]=1.Cl.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[CH2:10][CH2:9][C:8]([C:17]([OH:19])=[O:18])=[CH:7][C:6]=2[CH:24]=1
Reactant: CCOCCN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOCCN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Reaction time: 24 h
Yield: 77.3 %

Procedure:
In ethyl acetate (22 ml) was dissolved tert-butyl 7-bromo-1-(2-ethoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.1 g). To the solution was added 4N hydrochloric acid/ethyl acetate (11 ml) at room temperature, and the mixture was stirred for 24 hours. An aqueous saturated solution of sodium hydrogen carbonate was added to adjust pH to approximate 4, followed by extraction with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=8/1) to give 7-bromo-1-(2-ethoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.73 g).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC1(C)O[C@H]2[C@@H]3OC(C)(C)O[C@]3(C(O)=O)O[C@H]2C[O:11]1.O.OO.NC(N)=O>ClCCl>[C:3]1([CH:2]2[CH2:1][O:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(C)OC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O1
Reactant: C=Cc1ccccc1
Agent: NC(N)=O
Agent: OO
Solvent: O
Solvent: ClCCl
Product: c1ccc(C2CO2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
Styrene (1 g, 9.6 mmol) was taken with 100 mg Immobilized lipase and 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate (0.3 g, 1.03 mmol) in dry dichloromethane (15 mL) and stirred at 25° C. and added urea hydrogen peroxide (3 g, 32 mmol) portion-wise at a pH 5 for 20 hours. The reaction was monitored occasionally on TLC. The mixture was filtered and washed the residue with dichloromethane and the filtrate was reduced its volume under reduced pressure using vacuum flash evaporator. The product was purified by preparative TLC with 40% CH2Cl2/hexane. Yield: 70%; oil (Found: C, 79.91; H, 6.65. C8H8O requires C, 79.97; H, 6.71%); Rf (40% CH2Cl2/hexane) 0.55. The enantiomeric excess was determined by HPLC analysis using a Chiralcel OD column [iPrOH:hexane=0.2:99.8, flow rate 0.2 cm3 min−1], [α]D22+21.6 (c 0.7, PhH) 48% ee; {lit., [α]D22+44.8 (c 1.00, PhH), R}; νmax (neat/cm−1) 1496, 1476, 1452, 1390; δH (300 MHz; CDCl3) 2.80 (1H, dd, J 2.6 and 5.5, HCOCHH), 3.13 (1H, dd, J 4.1 and 5.5, HCOCHH), 3.85 (1H, dd, J 2.6 and 4.0, PhCHOCH2), 7.26-7.36 (5H, m, 5×CH, arom.); δC (300 MHz; CDCl3) 51.7 (CH2), 52.8 (CH), 125.9, 126.3, 128.6, 128.9 and 138.0 (6×C-Ph). MS m/z (rel. intensity %): 122 (M+2, 15), 121 (M+1, 43), 120 (M+, 20), 105(100), 91(68), 77 (88).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][C:15]=2[Cl:21])[C:6]=1/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.CCCCCC.C(OCC)(=O)C>C(NC(C)C)(C)C.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.[Cu](I)I>[Cl:1][C:2]1[N:3]=[C:4]([CH3:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:16][C:15]=2[Cl:21])[C:6]=1/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(I)cc1Cl
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(C#Cc2ccccc2)cc1Cl

Procedure:
To a mixture of methyl (E)-3-(4-chloro-1-(2-chloro-4-iodobenzyl)-2-methylimidazol-5-yl)-2-propenate (360 mg), dichlorobis(triphenylphosphine)palladium(II) (28 mg) and copper iodide (7.6 mg) was added a solution of phenylacetylene (326 mg) in diisopropylamine (20 ml) in a nitrogen atmosphere and the mixture was ref luxed under heating for 5 hr. The reaction mixture was allowed to cool. Water was added and the mixture was extracted twice with chloroform. The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The resultant was filtrated under reduced pressure and concentrated to give a crude product. The product was applied to flash silica gel column chromatography (silica gel 10 g) to give methyl (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-methylimidazol-5-yl)-2-propenate as brown amorphous (331 mg) from the eluted fraction of hexane/ethyl acetate=5/1–1-1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].N[C@H]1COC2C=C(C)C=CC=2NC1=O.C(OC([NH:29][C@@H:30]([C@@H:34]([OH:36])[CH3:35])[C:31](O)=[O:32])=O)(C)(C)C.F[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][C:39]=1[N+:48]([O-])=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:29][C@H:30]1[C@H:34]([CH3:35])[O:36][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][C:39]=2[NH:48][C:31]1=[O:32]
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: Cc1ccc2c(c1)OC[C@H](N)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1Oc2ccc(C(F)(F)F)cc2NC(=O)[C@H]1N
Reaction time: 8 h

Procedure:
In a similar manner to that described for the preparation of (S)-3-amino-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate except in Step 1 the mixture was stirred overnight and in Step 2 the mixture was stirred 3 h, (2S,3S)-2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid discyclohexylamine salt (2.0 g, 5.00 mmol) and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.04 g, 5.00 mmol) were converted to the title compound (58 mg) which was used without purification.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[NH2:8][C:9](=[NH:42])[N:10]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@H:12]([C:22]([N:24]2[CH2:28][CH2:27][C@H:26]([N:29]([C@H:35]3[CH2:40][CH2:39][C@@H:38]([CH3:41])[CH2:37][CH2:36]3)[C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:25]2)=[O:23])[CH2:11]1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:2]([NH:42][C:9](=[NH:8])[N:10]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@H:12]([C:22]([N:24]2[CH2:28][CH2:27][C@H:26]([N:29]([C@H:35]3[CH2:36][CH2:37][C@@H:38]([CH3:41])[CH2:39][CH2:40]3)[C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:25]2)=[O:23])[CH2:11]1)(=[O:1])[CH3:4]
Reactant: CC(C)C(=O)N([C@H]1CCN(C(=O)[C@@H]2CN(C(=N)N)C[C@H]2c2ccc(Cl)cc2)C1)[C@H]1CC[C@@H](C)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC(=N)N1C[C@@H](C(=O)N2CC[C@H](N(C(=O)C(C)C)[C@H]3CC[C@@H](C)CC3)C2)[C@H](c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-[(3S)-1-{[(3S,4R)-1-[amino(imino)methyl]-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}pyrrolidine-3-yl]-2-methyl-N-(cis-4-methylcyclohexyl)propaneamide TFA salt (185 mg, 0.3 mmol) prepared in Example E9 in DCM (3 ml) was added acetic acid anhydride (46 mg, 0.45 mmol) and TEA (71 mg, 0.7 mmol), and stirred at rt for 6 h. After the reaction finished, the solvent was concentrated in vacuo, extracted with water and EtOAc, and the organic layer was dried over MgSO4. The organic solution was concentrated in vacuo, and purified by HPLC to give the title compound (139 mg, 85%).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[C:9]2[C:10]([Cl:17])=[CH:11][C:12]([O:15]C)=[C:13]([Cl:14])[C:8]=2[S:7][CH:6]=1.CC([S-])(C)C.[Na+]>CN(C=O)C>[Cl:17][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:18])=[O:2])=[CH:6][S:7][C:8]=2[C:13]([Cl:14])=[C:12]([OH:15])[CH:11]=1
Reactant: COC(=O)Cc1csc2c(Cl)c(OC)cc(Cl)c12
Agent: CC(C)(C)[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1csc2c(Cl)c(O)cc(Cl)c12
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 119.7 %

Procedure:
A mixture of methyl(4,7-dichloro-6-methoxy-1-benzothiophen-3-yl)acetate (300.9 mg), DMF (dry) (9.0 mL) and sodium 2-methyl-2-propanethiolate (442 mg) was stirred at 160° C. for 20 min. The mixture was quenched with water and 1N HCl and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo to give (4,7-dichloro-6-hydroxy-1-benzothiophen-3-yl)acetic acid (327 mg) as a crude mixture. A crude mixture of (4,7-dichloro-6-hydroxy-1-benzothiophen-3-yl)acetic acid (369 mg) was dissolved in MeOH (10 mL). To the solution was added conc. H2SO4 (0.100 mL). The mixture was stirred at 80° C. for 40 min. The mixture was concentrated. The residue was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The solid was washed with hexane to give the title compound (345 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@H:35]([CH:38]([CH3:40])[CH3:39])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@@H:35]([CH2:36][OH:37])[CH:38]([CH3:40])[CH3:39])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC(C)[C@@H](N)CO
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@@H](CO)C(C)C)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (R)-2-amino-3-methyl-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H37N6O5SF2 [(M+H)+] 571.2509, observed 571.2514.
Reaction SMILES: [C:1]([C:3]([C:17]#[N:18])=[CH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)#[N:2].C(O)C.[C-:22]#[N:23].[Na+]>O.C(O)(=O)C>[C:1]([CH:3]([C:17]#[N:18])[CH:4]([C:22]#[N:23])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)#[N:2]
Reactant: [C-]#N
Reactant: COc1cc(C=C(C#N)C#N)cc(OC)c1OC
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C(C#N)C(C#N)C#N)cc(OC)c1OC

Procedure:
To a suspension of 1,1-dicyano-2-(3,4,5-trimethoxyphenyl) ethene (8.5 g, 0.035 moles) in boiling ethanol (150 ml), sodium cyanide (1.77 g, 0.0351 moles) was added dropwise from a pipette. A dark solution formed which was additioned with distilled water (500 ml) and acidified with glacial acetic acid (to pH2) at room temperature. No precipitate formed. With stirring, water (20 ml) was added, consequently precipitating out dirty white crystals. The crystals were filtered, washed repeatedly with water (500 ml) and dried in a vacuum oven. The product was recrystallised from ethanol.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[S:17][CH:16]=[CH:15][C:11]=3[N:12]([CH3:14])[N:13]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>ClCCl>[CH3:14][N:12]1[C:11]2[CH:15]=[CH:16][S:17][C:10]=2[C:9]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)=[N:13]1
Reactant: COc1cccc(-c2nn(C)c3ccsc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1nc(-c2cccc(O)c2)c2sccc21
Reaction time: 2.5 h
Yield: 49 %

Procedure:
Treat a stirred solution of 3-(3-methoxyphenyl)-1-methyl-1H-thieno[3,2-c]pyrazole (7.5 g, 0.031 mol.) and dichloromethane (51 mL) dropwise with a solution of boron tribromide (41 mL, 0.041 mol., 1.0M in dichloromethane) under nitrogen. After 2.5 hours, quench with hydrochloric acid (50 mL, 1N) and ether/ethyl acetate (50 mL), and stir until both phases are clear. Wash the organic phase with water, dry (MgSO4), filter and evaporate to give an oil. Purify the oil by HPLC (silica gel, elution with 10% methanol in dichloromethane) to give a light tan solid. Purify the solid further by column chromatography (silica gel, elution with 5% methanol in dichloromethane) to give a white solid (3.5 g, 49% yield).
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22]1.C(N(C(C)C)CC)(C)C.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[CH2:46][C:47](Cl)=[O:48]>>[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[CH2:46][C:47]([N:25]1[CH2:26][CH:21]([CH3:20])[CH2:22][CH:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24]1)=[O:48]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCOC(=O)C1CNCC(C)C1
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CC(C)CN(C(=O)Cc2cccs2)C1
Yield: 74 %

Procedure:
This reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl 5-methyl-3-piperidinecarboxylate (311 mg; 1.82 mmol), diisopropylethylamine (350 μl; 2.01 mmol), and thiopheneacetyl chloride (225 μl; 1.83 mmol). Crude product was purified by distillation at approximately 220° C./0.1 torr, giving ethyl 1-(2-thiopheneacetyl)-5-methyl-3-piperidinecarboxylate (398 mg) as a yellow oil. MS m/z (positive ion) 467 (25), 296 (MH+; 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([N:24]([CH3:26])[CH3:25])=O)[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.[B].O1CCCC1.[Cl-].[NH4+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:24]([CH3:26])[CH3:25])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: CN(C)C(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [B]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 13 h
Yield: 28.5 %

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxamide (200 mg, 0.513 mmol) was added boron-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran, 2.6 mL, 2.6 mmol), and the mixture was stirred at 70° C. for 13 hr. To the mixture was added aqueous saturated ammonium chloride, and the mixture was stirred at 70° C. for 20 min. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with diisopropyl ether to give the title compound as a colorless powder (54.8 mg, 0.146 mmol, 28%).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][P:10]([C:15](Cl)([Cl:22])[C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])([O:12][CH2:13][CH3:14])=[O:11])[CH3:8].C(Cl)(Cl)Cl>O.C(O)C>[CH2:7]([O:9][P:10]([CH:15]([Cl:22])[C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])([O:12][CH2:13][CH3:14])=[O:11])[CH3:8]
Reactant: CCCOC(=O)C(Cl)(Cl)P(=O)(OCC)OCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CCCOC(=O)C(Cl)P(=O)(OCC)OCC
Temperature: 8 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
A solution of sodium sulphite (78.6 g) in water (2000 cm3) was added dropwise to a cooled solution of propyl diethylphosphonodichloroacetate (95.7 g) in ethanol (408cm3) over a period of 70 minutes, the temperature of the mixture being maintained below 8° C. during the addition by external cooling. The mixture was stirred at 8° C. for 10 minutes, then without external cooling for a further 15 minutes. Chloroform (100cm3) was added and the mixture stirred vigourously for 3 minutes. The chloroform phase was separated and combined with further chloroform extracts of the aqueous phase, The combined organic layers were dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure to give the crude product as a yellow oil from which volatile compounds were removed by storage under high vacuum. The crude product was purified by distillation under reduced pressure to give a colourless liquid (75.2 g)