Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12](=[O:18])[NH:13][CH:14]=[CH:15][C:16]=1[I:17])=O.O=P(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C:11]1[C:12](=[O:18])[NH:13][CH:14]=[CH:15][C:16]=1[I:17]
Reactant: Nc1ccncc1NC(=O)c1c(I)cc[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1[nH]ccc(I)c1-c1nc2cnccc2[nH]1
Reaction time: 2 h

Procedure:
To a solution of 4-iodo-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (4-amino-pyridin-3-yl)-amide (281 mg, 0.79 mmol) in 9 mL pyridine at 0 C was added (slowly) 0.5 mL POCl3 (5.3 mmol). The mixture was stirred at 0 C for 2 hours, then poured on a mixture of ice and saturated aqueous sodium bicarbonate solution. The product precipitates as a colloid. All attempts to filter or extract the product failed. The mixture was concentrated in vacuum, water removed by aceotropic destillation with n-propanol and the crude mixture used as it is. LCMS [M+H]+ 339, T=0.54 min product and [M+H]+ 357, T=0.29 min unreacted starting material [YMC ODS-A C18 S7 3.0×50 mm column; 0-100% gradient over 2 min*; 5 mL/min flow rate]. * Gradient begins with 10% methanol/90% water (0.1% TFA) and end with 90% methanol/10% water (0.1% TFA)
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[C:17]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:33]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[N:32][N:31]=4)=[CH:25][CH:24]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:4][C:5]([NH:8]C(=O)OC(C)(C)C)=[N:6][CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:8][C:5]1[N:4]=[C:3]([C:16]2[C:17]([O:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:33]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[N:32][N:31]=4)=[CH:27][CH:28]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[C:2]([F:1])=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(F)c(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(F)c(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a RBF, tert-butyl 5-fluoro-4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylcarbamate (1.46 g, 2.43 mmol) was dissolved in DCM (4.86 ml, 2.43 mmol). TFA (749 μl, 9.72 mmol) was added at RT. The reaction was stirred at RT. After 20 min, LCMS showed mainly starting material. 1 mL of TFA was added and the reaction was allowed to stir at RT overnight. After 16 h, the reaction was concentrated and the residue dissolved in DCM. The solution was cooled to 0° C. and neutralized with 2N NaOH. At pH=5-7, the product as a white solid precipitated out. At pH>7, the product dissolves in DCM. The precipitate was filtered with aid of DCM. The solid product was set aside, while the filtrate was concentrated. The residue was diluted with a bit of DCM. Water was added. Ether was added and the whole solution was triturated to precipitate out additional product. The solid was filtered off with an aid of Et2O. This crop was combined with the first crop of solid. The product was purified by column chromatography on 120 g silica gel using 70:30 DCM:(90:10:1 DCM:MeOH:NH4OH). Fractions containing the product were combined, and concentrated, to afford an off white solid, which was triturated in Et2O. The resulting yellow solid was filtered off with an aid of Et2O and air dried. The solids were purified further via RPLC on the acidic Gilson Only fractions containing the product were combined, diluted with DCM, and washed with sat. NaHCO3. The organic was dried over MgSO4, filtered, and concentrated to afford N-(4-(3-(2-amino-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine. MS Calcd for C29H20FN7O: [M]+=501. Found: [M+1]+=502.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH:21][C:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([CH3:24])[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CCOC(C)=O>[OH:20][C@H:3]([CH2:2][NH:1][CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([C:22]([OH:21])([CH3:23])[CH3:24])[CH:26]=1)[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Reactant: CC(C)(O)c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A solution of tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (230 mg, 0.82 mmol) in THF was added 3-(2-hydroxypropan-2-yl)benzaldehyde (180 mg, 01.06 mmol) and stirred for 30 min at room temperature, NaB(OAc)3H (302.5 mg, 1.43 mmol) was then added portionwise in 30 min, and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was separated and dried (Na2SO4). Concentration in vacuo, followed purification with flash chromatography to give the desired product as a white solid (230 mg, 65% yield). 1H NMR (CDCl3): d: 8.514 (m, 2H), 7.717 (s, 1H), 7.321-7.203 (m, 5H), 3.831 (s, 3H), 3.580 (m, 1H), 2.978 (m, 1H), 2.890-2.755 (m, 3H), 1.724 (d, J=11.1 Hz, 6H), 1.364 (s, 9H).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[C:11]([CH3:17])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([N:7]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[C:11]([CH3:17])[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C(=O)N(C2CCCCC2)C2CCCC2)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)N(C2CCCCC2)C2CCCC2)ccc1CO
Temperature: 0 °C
Yield: 106.7 %

Procedure:
The aldehyde XXXIV of Scheme K (1.70 g, 0.0052 moles) was dissolved in 20 mls of MeOH and cooled to 0° C. under argon. NaBH4 (110 mg) was added and the mixture was allowed to warm to 25° C. Excess solvent was removed under vacuum and the residue was treated with water and ethyl acetate. The organic layer was separated and dried (Na2SO4). Removal of the solvent on the rotary evaporator gave a residue which was chromatographed on silica gel using 30% ethyl acetate/hexane as the eluent to give 1.75 g (96%) of the title compound as an oil. NMR (ppm, CDCl3): 2.28 (3H, s); 4.65 (2H, s); 7.10 (1H, d, J=8 Hz); 7.15 (1 h, s); 7.30 (1 h, d, J=8 Hz).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNS(C)(=O)=O)C1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in THF (2 mL) were added triethylamine (60.7 mg) and methanesulfonyl chloride (68.7 mg) under ice-cooling, and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure, distilled water was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (161 mg).
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].Cl[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1>>[F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][O:4][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1
Reactant: OCC(F)(F)C(F)F
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc(OCC(F)(F)C(F)F)nc1

Procedure:
In a similar manner to that described in Reference example 1(c), a reaction was carried out using 2,2,3,3-tetrafluoropropanol (5.23 ml), sodium hydride (55% suspension in oil, 1.91 g) and methyl 6-chloronicotinate (5.00 g) and treated to afford crude methyl 6-(2,2,3,3-tetrafluoropropoxy)nicotinate (5.42 g) as a colorless oil. In a similar manner to that described in Example 2, a reaction was carried out using the crude product described above (2.70 g) and aqueous sodium hydroxide solution (2N, 15 ml) and the reaction mixture was treated to afford crude title compound (1.60 g). This product was used in Example 102 and Example 150 without further purification.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:18]2([O:20][CH2:19]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CO>[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:18]([CH2:19][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([OH:20])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CO2)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)(CNCc2ccccc2)C1
Yield: 100 %

Procedure:
Benzyl amine (1.7 mL, 1.1 eq) was added to a solution of rac-1-oxa-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (commercial, 2.80 g, 14.05 mmol) in MeOH (25 mL) and the mixture was heated at reflux for 2 h. The resulting solution was concentrated under reduced pressure and the residue was purified by CC (DCM-MeOH—NH4OH 1000:50:4) to afford the title compound as colourless oil (4.29 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CC(N(C)C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[C:4]=2[F:9])[CH:21]=[CH:20][N:19]=1
Reactant: Nc1ccc(O)c(F)c1F
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
4-amino-2,3-difluorophenol (6 g, 41.4 mmol) and potassium tert-butoxide (4.9 g, 43.5 mmol) were suspended in DMAc (200 mL) and stirred at RT for 30 min under Ar atmosphere. 2,4-Dichloropyridine (6.1 g, 41.4 mmol) was added, and the resulting mixture was heated at 70° C. for 8 h. The reaction mixture was filtered, concentrated in vacuo and purified by silica gel chromatography to afford 4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (7 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, J=6.0 Hz, 1 H), 7.05 (s, 1 H), 6.95 (m, 1 H), 6.92 (m, 1 H), 6.62 (m, 1 H), 5.60 (s, 2 H); MS (ESI) m/z: 257.1[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][C:44]([F:47])([F:46])[F:45])[CH:40]=[CH:39][C:38]=1[S:48](Cl)(=[O:50])=[O:49]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:48]([C:38]1[CH:39]=[CH:40][C:41]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:42][C:37]=1[O:36][CH3:35])(=[O:49])=[O:50])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:15][CH2:16][CH:17]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: COc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: COc1ccccc1C1(CC(=O)N2CCC(c3ccncc3)CC2)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(CC(=O)N2CCC(c3ccncc3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2OC)c2ccc(Cl)cc21
Yield: 38.9 %

Procedure:
With 290 mg of 5-chloro-3-(2-methoxyphenyl)-3-[2-oxo-2-(4-pyridin-4-yl piperidin-1-yl)ethyl]-1,3-dihydro-2H-indol-2-one obtained in Step 51-2 and 195 mg of 2-methoxy-4-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 173 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 1.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:23]1([N:9]([CH:6]2[CH2:7][CH2:8][N:3]([C:1](=[NH:2])[NH:27][OH:28])[CH2:4][CH2:5]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide (200 mg), hydroxylamine hydrochloride (70 mg), and potassium carbonate (82 mg) in ethanol (0.70 mL) and water (1.00 mL) is heated under reflux for 5 h. The reaction mixture is cooled to room temperature, stirred at this temperature for two days and concentrated in vacuo. The residue is mixed with water and ethyl acetate and the organic phase is separated, dried and concentrated in vacuo. The crude product is purified by HPLC (MeOH/H2O/TFA). LC (method 3): tR=1.35 min; Mass spectrum (ESI+): m/z=370 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CCCCBr
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCNc1ccccc1-c1ccccc1
Yield: 91 %

Procedure:
50.0 g of 2-aminobiphenyl, 38.2 g of ethyldiisopropylamine and 61.9 g of ethyl 5-bromovalerate are reacted analogously to Example 47a) to obtain 80.0 g of ethyl 5-(biphenyl-2-yl)aminovalerate as a non-crystallizing oil.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([Cl:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:28][C:25]([F:26])([F:27])[C:22]1[N:20]2[N:21]=[C:16]([N:12]3[CH2:11][CH2:10][N:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:14][CH2:13]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Reactant: c1ccc(CCN2CCNCC2)cc1
Product: FC(F)(Cl)c1nnc2ccc(N3CCN(CCc4ccccc4)CC3)nn12
Yield: 71 %

Procedure:
A mixture of 1-phenethylpiperazine and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 3-[chloro(difluoro)methyl]-6-[4-(2-phenylethyl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 71% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[N:13](OCCCC)=[O:14].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])/[C:7](=[N:13]\[OH:14])/[CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCCCON=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)C/C(=N/O)C2=O
Reaction time: 0.5 h

Procedure:
To a solution of 5-(methyloxy)-2,3-dihydro-1H-inden-1-one (1.0 g, 6.2 mmol) in methanol (15 mL) at 40 degrees Centigrade was added n-butyl nitrite (0.8 mL, 6.25 mmol) followed by concentrated HCl (0.6 mL). The reaction was stirred for 30 min during which time a precipitate formed, collected, dried and used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].S(=O)(=O)(O)O>CCOC(C)=O>[CH2:1]([O:3][C:4]([C@@:6]1([NH2:11])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Temperature: 8 °C
Reaction time: 1 h

Procedure:
A suspension of 5.11 g (20.0 mmol) of (1R,2S)-1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (commercially available from Synthetech Oregon, USA) in 1.94 mL of EtOAc was cooled to 8° C. using an ice bath and a solution of 2.17 g (21.0 mmol) of sulfuric acid in 4.0 mL of EtOAc was added in 5 min. The ice bath was removed and the reaction mixture was stirred for 30 min at RT and 1 h at 50° C. The reaction mixture was then cooled to RT and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][CH3:33])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH2:31][CH2:32][CH3:33])[C:34](=[O:36])[CH3:35])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(=O)Cl
Product: CCCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(C)=O
Yield: 70 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(propylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 70% yield; NMR spectrum (DMSO-d6) 0.82 (t, 3H), 1.53-1.59 (m, 2H), 1.97 (s, 3H), 3.27 (s, 2H), 3.86 (t, 2H), 4.39 (t, 2H), 5.31 (s, 2H), 7.17 (d, 1H), 7.25 (d, 1H), 7.33-7.39 (m, 2H), 7.58-7.60 (m, 2H), 7.71-7.75 (m, 1H), 7.87-7.91 (m, 1H), 7.95 (d, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 506.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][NH:33][CH:34]1[CH2:38][N:37]([CH3:39])[CH2:36][CH2:35]1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:33]([CH3:32])[CH:34]4[CH2:35][CH2:36][N:37]([CH3:39])[CH2:38]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CNC1CCN(C)C1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N(C)C2CCN(C)C2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 27.4 mg (0.24 mmol) N,N′-dimethyl-3-aminopyrrolidine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 25 mg (38%) product as an orange powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]2[C:6](=[C:8]([C:12]([OH:14])=O)[CH:9]=[CH:10][CH:11]=2)[N:7]=1.Cl.Cl.[NH2:17][C@H:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1>>[N:20]12[CH2:19][C@@H:18]([NH:17][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:5]4[O:4][C:3]([S:2][CH3:1])=[N:7][C:6]=34)=[O:14])[CH:23]([CH2:24][CH2:25]1)[CH2:22][CH2:21]2
Reactant: CSc1nc2c(C(=O)O)cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: CSc1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1

Procedure:
Following general procedure GP-C1, a mixture of 2-(methylthio)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(methylthio)benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Mg].[C:2]([O:8][CH:9]([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:12](Cl)(=[O:14])[CH3:13].S(=O)(=O)(O)O>C(O)C.ClC(Cl)(Cl)Cl>[C:4]([CH:3]([C:12]([CH3:13])=[O:14])[C:2]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])(=[O:5])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC(=O)CC(=O)OC(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CC(=O)C(C(C)=O)C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
5 ml of tetrachloromethane are added to 23.3 g (1 mol) of magnesium turnings in 50 ml of dry ethanol under nitrogen and in the absence of moisture. After the beginning of gas evolution, a solution of 147.1 g (1 mol) of isopropyl acetoacetate in 100 ml of dry ethanol was slowly added dropwise, the reaction mixture being kept at the reflux temperature. Stirring was carried out for a further 4 hours at this temperature, after which the mixture was cooled. 78.5 g (1 mol) of acetyl chloride was slowly added dropwise at 10° C. Stirring was continued for a further 4 hours at room temperature and hydrolysis was then effected with a mixture of 450 ml of ice water and 25 ml of concentrated sulfuric acid. The organic phase was separated off, dried, and evaporated down under reduced pressure. 192.3 g of >96% pure isopropyl 2-acetylacetoacetate were obtained.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15](=[O:22])[CH:16]=[CH:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH3:13].[N+:23]([CH3:26])([O-:25])=[O:24]>CC#N>[CH2:12]([O:14][C:15](=[O:22])[CH2:16][CH:17]([CH2:26][N+:23]([O-:25])=[O:24])[CH2:18][CH:19]1[CH2:20][CH2:21]1)[CH3:13]
Reactant: CCOC(=O)C=CCC1CC1
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC(CC1CC1)C[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
DBU (4.1 g, 26.9 mmol) is added to a solution of 4-cyclopropyl-2-butenoic acid ethyl ester (3.4 g, 26.9 mmol) and nitromethane (9.13 g, 135 mmol) in 20 mL of CH3CN. The solution is warmed to 60° C. under Ar for 4 hours, then stirred at room temperature overnight. The CH3CN is evaporated, and the residue is taken up in 50 mL of EtOAc. The solution is washed with saturated KH2PO4 (3×50 mL) followed by 50 mL of brine. The organic layer is dried over Na2SO4 and evaporated to give an oil which is chromatographed (MPLC) over silica gel with 25% EtOAc/hexane to give 2.4 g of 4-cyclopropyl-3-nitromethyl-butanoic acid ethyl ester 3.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C@H:11]([NH:13][C:14]2[C:15]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=4)[NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[NH:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C@@H:11]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH3:12])[C:15]=3[CH:22]=2)=[CH:28][CH:27]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CO)cc3)cc12)c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CCl)cc3)cc12)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of thionyl chloride (25.7 ml, 0.328 mol) in 180 ml of toluene is cooled to −10° C. Solid {4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol (11.3 g, 0.0328 mol) is added in 8 portions over a range of 1 h. The temperature is then increased slowly to 0° C. and the mixture stirred for 2 h. The cold reaction mixture is filtered and the solid washed with toluene and ether. The crude product is suspended in water and treated with saturated sodium bicarbonate solution until the mixture turns basic. The mixture is stirred well for about 10 min and filtered. The solid is thoroughly washed with water and dried under reduced pressure to give the title compound; m.p.>320° C.; Rf(dichloromethane/ethanol 9:1)=0.46; HPLC tR=10.63 min; MS-ES+: (M+H)+=363.