Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1.[O:12]=[C:13]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:14]1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[OH:12][C:13]1([CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[O:3])[CH2:14][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:16]1
Reactant: C[Si](C)(C)OC1=CCCCC1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1CCCCC1C1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
A solution of 1-(trimethylsiloxy)cyclohexene (200 mg, 1.17 mmol) and benzyl 3-oxoazetidine-1-carboxylate (289 mg, 1.41 mmol), prepared using procedures similar to those described in Reference 3, in tetrahydrofuran (3.90 mL) was cooled to −78° C. for 10 minutes followed by the addition of titanium tetrachloride (0.13 mL, 1.17 mmol). The reaction mixture stirred for an additional 5 hours at −78° C. The mixture was quenched with aqueous sodium bicarbonate and the aqueous layer was extracted with ether (2×). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified on silica gel chromatography column (3:2 hexanes/ethyl acetate) to afford benzyl 3-hydroxy-3-(2-oxocyclohexyl)azetidine-1-carboxylate (328 mg, 37%). 1H NMR (CDCl3): 7.28-7.34 (m, 5H), 5.08 (s, 2H), 4.02 (d, 1H), 3.89 (d, 1H), 3.87 (s, 1H), 3.55 (s, 1H), 2.71 (q, 1H), 2.29-2.43 (m, 2H), 2.11 (s, 2H), 1.95 (s, 1H), 1.66 (d, 3H); MS (EI) for C17H21NO4: 303 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:41][CH:42]([CH3:51])[C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44]>ClCCl>[C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:6]([C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=2)[CH:1]=[O:2])=[O:8])[CH2:47][CH2:46]1)(=[O:44])[CH:42]([CH3:51])[CH3:41]
Reactant: CC(C)C(=O)N1CCNCC1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
To a solution of 3-formylbenzoic acid (750 mg, 5 mmol) in anhydrous dichloromethane (15 mL) was added triethylamine (1.263 g, 12.5 mmol), 1-hydroxybenzotriazole (0.743 g, 5.5 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g, 5.5 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C., and 2-methyl-1-(piperazin-1-yl)propan-1-one (1.06 g, 5.5 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (50 mL×2), 10% citric acid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (1.44 g, yield: 95%) as a gum. LC-MS (ESI) m/z: 289 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25]S(C)(=O)=O)=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[OH-].[Na+].O.Cl>O1CCOCC1>[Cl:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(Cl)c3sc4ccccc4c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(-c2c3ccccc3c(Cl)c3sc4ccccc4c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
A biphasic mixture of methanesulfonic acid 4-(6-chloro-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (0.917 g, 2.09 mmol) in dioxane (13 mL) and a solution of sodium hydroxide (2.5 N, 6.7 mL, 16.7 mmol, 8 eq) was heated at reflux overnight. After cooling to room temperature the reaction mixture was combined with water (50 mL), acidified with concentrated hydrochloric acid, and stirred for 15 minutes. The crude white solid product was collected by filtration, redissolved in ether, combined with silica gel, and the solvent was removed. The adsorbate was flash chromatographed (gradient 85/15-80/20 petroleum ether/ethyl acetate) to give the title compound as a white solid (0.705 g, 94%); mp 193-195° C.; NMR (CDCl3); δ 8.37 (ddd, J=8, 1, Hz, 1H), 7.81 (ddd, J=8, 1, 1 Hz, 1H), 7.68-7.63 (m, 2H), 7.44 (ddd, J=8, 7, 1 Hz, 1H), 7.39 (ddd, J=8, 7, 1 Hz, 1H), 7.29-7.26 (m, 2H,), 7.14-7.09 (m, 3H), 6.81 (ddd, J=8, 1, 1 Hz, 1H), 5.01 (d, J=4 Hz, 1H); MS (+EI): [M+], 1 chlorine isotope pattern, 360 (100%), 362 (45%); Anal. calc. for C22H13ClOS: C, 73.23, H, 3.63, N, 0.00. Found: C, 72.86, H, 3.24, N, 0.04.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][NH:25][CH3:26]>C(O)(C)C.O>[CH3:24][N:25]([CH3:26])[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: CNC
Reactant: C[Si](C)(C)CCOCn1cnc2c(-c3ccco3)nc(Cl)nc21
Solvent: O
Solvent: CC(C)O
Product: CN(C)c1nc(-c2ccco2)c2ncn(COCC[Si](C)(C)C)c2n1
Yield: 86 %

Procedure:
A solution of 2-chloro-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine (488 mg, 1.4 mmol) in isopropanol (5 mL) was treated with 40% dimethylamine in water (1 mL), refluxed for 2 h, concentrated in vacuo and purified by chromatography [SiO2; EtOAc Heptane, (1:1)] to give the title compound (431 mg, 86%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C>[CH3:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:21]([NH:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:10])(=[O:19])=[O:18])=[O:22])[N:3]=1
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1nc(C)nc(N)n1
Solvent: CC#N
Product: Cc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C)n1

Procedure:
To 12.3 g 2-amino-4,6-dimethyl-1,3,5-triazine in 250 ml of dry acetonitrile was added, with stirring, 19.7 g of 2-methylbenzenesulfonyl isocyanate at a rate designed to avoid excessive heating of the reaction mixture. Stirring was continued until the desired product crystallized. The product was removed by filtration, washed with a small amount of ethyl ether and dried. The resulting product, N-[(4,6-dimethyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-methylbenzenesulfonamide, melted at 141°-145° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:16]([O-])=O)=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[NH2:16][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:13][C:12]=1[C:14]#[N:15]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(C#N)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(N)c(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(4-Methylpiperazinyl)-2-nitrobenzenecarbonitrile (1.0 equivalent) was dissolved in EtOAc. The flask was purged with nitrogen, and 10% Pd/C (0.1 equivalents) was added. The flask was evacuated and purged with H2 three times. The resulting mixture was stirred for three days at room temperature. The mixture was filtered through Celite and the filter pad was washed with EtOAc. The solvent was removed in vacuo to give a yellow solid which was purified by silica gel chromatography (5:1:95 MeOH:Et3N:EtOAc) to give the desired product as a yellow solid. LC/MS m/z 217.3 (MH+), Rt 0.95 minutes.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([OH:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[N:16].[CH3:18][S:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OCC)=[O:31])=[CH:25][CH:24]=1)(=[O:21])=[O:20]>>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH:6]([OH:17])[CH2:5][NH:4][CH2:3][CH2:2][NH:1][C:30](=[O:31])[CH2:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][S:19]([CH3:18])(=[O:20])=[O:21])=[CH:28][CH:27]=1)#[N:16]
Reactant: CCOC(=O)Cc1ccc(NS(C)(=O)=O)cc1
Reactant: N#Cc1ccccc1OCC(O)CNCCN
Product: CS(=O)(=O)Nc1ccc(CC(=O)NCCNCC(O)COc2ccccc2C#N)cc1

Procedure:
In a similar manner using 1.2 g. of 3-(β-aminoethylamino)-1-(2-cyanophenoxy)-2-propanol and 1.29 g. of ethyl 4-methanesulphonamidophenylacetate as starting materials there is obtained 1-(2-cyanophenoxy)-3-β-(4-methanesulphonamidophenylacetamido)ethylamino-2-propanol, isolated as its oxalate, m.p. 180°-182° C. after crystallisation from isopropanol.
Reaction SMILES: Cl[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[N-:11]=[N+:12]=[N-:13].[Na+].O>CS(C)=O.[N-]=[N+]=[N-].[Na+]>[N:11]([CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[N+:12]=[N-:13]
Reactant: O[C@H](CCl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@@H](O)c1ccccc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 96.8 %

Procedure:
(S)-α-(Chloromethyl)benzenemethanol (2.38 g) in dry DMSO (50 ml) was treated with sodium azide (1.48 g) with stirring then heated at 60° C. for 24 h. More sodium azide (74 mg) was added and heating continued at 80° C. for a further 24 h. The reaction mixture was cooled, poured into water and extracted into ethyl acetate, which was washed with water (3×) then brine and dried (MgSO4). The solvent was evaporated to give the sub-title compound (2.40 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].CCN(C(C)C)C(C)C.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S([O-])([O-])(=O)=O.[Mg+2]>CN(C=O)C>[CH2:17]([NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: COC(=O)CN
Reactant: CCCCCCCCBr
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCCNCC(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
Under argon condition, glycine methyl ester (358 mg, 2.85 mmol) was dissolved in 2 mL of dry DMF, and then DIPEA (620 μL, 3.56 mmol) and 1-bromooctane (123 μL, 0.712 mmol) were added, and the reaction mixture was stirred for one day at room temperature. Upon completion of the reaction, the reaction was terminated by adding 5 mL of water, and the reaction mixture was extracted with diethyl ether (4 mL×4). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 31.6 mg (0.157 mmol, 22%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](Cl)(=[O:13])=[O:12])[C:7](=[O:15])[CH2:6][CH2:5]2.[NH3:16]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:13])(=[O:12])[NH2:16])[C:7](=[O:15])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)c(S(=O)(=O)Cl)cc21
Reactant: N
Product: NS(=O)(=O)c1cc2c(cc1Cl)CCC2=O

Procedure:
99.6 Grams of 5-chloro-6-chlorosulfonyl-1-indanone are introduced portionwise into 700 ml of liquid ammonia. The solvent is allowed to evaporate and the residue is dissolved in water, is heated within a short time on the water-bath and is filtered after the addition of active charcoal. The solution is acidified with hydrochloric acid to a pH of 2, the precipitate is filtered off with suction and is washed with water. The melting point of 5-chloro-6-sulfamoyl-1-indanone is in the range of from 205° to 208° C., and after recrystallization from a mixture of acetone and water it is 216° to 218° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.N12CCCN=C1CCCCC2.[C:18]([CH:20]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)#[N:19]>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:21]2([CH2:20][C:18]#[N:19])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:25][CH2:26]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Reactant: Brc1cn[nH]c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(Br)cn2)CC1
Yield: 62.7 %

Procedure:
4-bromo-1H-pyrazole (362 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.368 ml) and tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (547 mg) in acetonitrile (10 ml) were stirred at 45° C. for 6 hours. The crude reaction was concentrated on dicalite (diatomaceous earth) and was purified by flash chromatography on silica gel eluting with 0 to 20% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-(4-bromopyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (570 mg) as a white foam. NMR Spectrum: (DMSO-d6) 1.45 (s, 9H), 1.94-2.04 (m, 2H), 2.54-2.62 (m, 2H), 2.80 (s, 2H), 2.93-3.04 (m, 2H), 3.88 (bs, 2H), 7.57 (s, 1H), 7.73 (s, 1H)
Reaction SMILES: [C:1]1([C:7]2[CH2:8][C:9](=O)[CH2:10][S:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>CO>[NH2:20][C:9]1[CH2:10][S:11][CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: [BH3-]C#N
Reactant: O=C1CSC=C(c2ccccc2)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1=CC(c2ccccc2)=CSC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
This compound was prepared as shown in Scheme 25. Thus, to 0.96 g (5 mmol) of 5-phenyl-3-thiopyranone (P. T. Lansbury, et al., J. Am. Chem. Soc. 1970, 92, 5649) in 50 mL of anhydrous methanol was added 7.7 g (100 mmol) of ammonium acetate and 6.5 g of 3A molecular sieves. After stirring 30 minutes at room temperature, 1.25 g (20 mmol) of sodium cyanoborohydride was added portionwise. After stirring 16 hours, the mixture was gravity filtered, and the methanol was evaporated under vacuum. The residue was partitioned between ice/HCl and ether. The acidic aqueous phase was extracted twice more with ether, then it was made basic with ice and 50% NaOH aqueous. The mixture was extracted with CH2Cl2, dried (MgSO4), and evaporated to give 0.19 g (20%) of the title compound. GC/MS showed 100% purity with a molecular ion of 193.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[N:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:12]1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:19][O:18][C:16]([C:13]1[N:14]=[CH:15][N:11]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:12]=1)=[O:17]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1nc[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ncn(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 12.1 g (77.1 mmol) 3-chlorophenylboronic acid and 10.0 g (77.1 mmol) methyl 1,2,4-triazole-3-carboxylate in 200 mL DCM was added 19.0 mL (235 mmol) pyridine followed by 14.0 g (77.1 mmol) copper (II) acetate. The reaction mixture was stirred at RT for 3 days, and then filtered over celite. The filtrate was washed with 1M aqueous KHSO4 solution and saturated aqueous bicarbonate solution. The organic layer was dried over sodium sulfate, concentrated in vacuo and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14](=[O:22])NC2C=CC=CN=2)=[C:12]([CH3:23])[NH:11][C:10]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[C:34]([CH3:35])=[N:33]C(C)=N3)=[CH:26][CH:25]=2)=[C:9]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].[OH-:42].[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([OH:22])=[O:42])=[C:12]([CH3:23])[NH:11][C:10]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[C:8]4[CH:13]=[CH:12][N:11]=[CH:10][C:9]=4[N:33]=[C:34]3[CH3:35])=[CH:26][CH:25]=2)=[C:9]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)C1=C(c2ccc(-n3nc(C)nc3C)cc2)NC(C)=C(C(=O)Nc2ccccn2)C1c1ccccc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccc(-n3c(C)nc4cnccc43)cc2)NC(C)=C(C(=O)O)C1c1ccccc1Cl
Yield: 81 %

Procedure:
A mixture of the (-)-cyanoethyl ester from (b), above, (271 mg, 0.566 mmol) and aqueous sodium hydroxide (2.54 ml, 0.55M, 1.40 mmol) in dioxane (7.5 ml) was stirred at room temperature under nitrogen for 1 hour. Hydrochloric acid (1.40 ml, 1M, 1.40 mmol) was added dropwise, and the mixture was concentrated under reduced pressure. The resulting yellow solid was suspended in water, filtered off, and dried in vacuo, to give the title compound, (200 mg, 81%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:19](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)\[CH2:20][CH2:21][Cl:22])=[CH:14][CH:13]=1)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:22][CH2:21][CH2:20]/[C:19](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:18](\[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:17][CH:16]=1)/[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCC/C(=C(/c1ccccc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCOc1ccc(/C(=C(\CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
6.9 g of E-1-[4-(2-benzyloxyethoxy)phenyl]-4-chloro-1,2-diphenyl-but-1-ene was dissolved in the mixture of ethyl acetate (60 ml) and ethanol (60 ml). Palladium on carbon (5%, 0.7 g) was added and the solution was stirred vigorously under a hydrogen atmosphere at room temperature until there was not any starting compound left (thin layer chromatography). Palladium on carbon was filtered off through siliceous earth and the filtrate was evaporated to dryness. The residue was crystallized several times from the mixture of ethanol and water.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].Br[CH:13]=[CH:14][CH2:15][CH2:16][CH3:17]>>[C:5]([CH:4]([CH2:17][CH2:16][CH2:15][CH:14]=[CH2:13])[C:3]([O:2][CH3:1])=[O:8])(=[O:7])[CH3:6]
Reactant: CCCC=CBr
Reactant: COC(=O)/C=C(\C)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: C=CCCCC(C(C)=O)C(=O)OC

Procedure:
Analogously to Example 14A, 10 g (72.4 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate (Example 13A) and 0.4 g (2.41 mmol) of potassium iodide are reacted with 10.8 g (72.4 mmol) of 1-bromopentene to give methyl 2-acetyl-6-heptenoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]2[CH:26]=[CH:25][N:24]3[N:27]=[CH:28][C:29]([C:30]([OH:32])=O)=[C:23]3[N:22]=2)[CH2:4][O:3]1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>>[CH:34]1([NH:37][C:30]([C:29]2[CH:28]=[N:27][N:24]3[CH:25]=[CH:26][C:21]([N:17]4[CH2:18][CH2:19][CH2:20][C@@H:16]4[C:10]4[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][CH:5]4[CH2:4][O:3][C:2]([CH3:33])([CH3:1])[O:6]4)=[N:22][C:23]=23)=[O:32])[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: CC1(C)OCC(COc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)O1
Product: CC1(C)OCC(COc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(C(=O)NC4CC4)c3n2)O1
Yield: 99 %

Procedure:
Prepared according to the method of Example 86, Step F, using 5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and cyclopropyl amine to yield the title compound as a white solid (33.0 mg, 99% yield). MS (apci) m/z=496.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:31]([CH2:30][CH2:29][CH2:28][CH2:27][Cl:26])(=[O:33])=[O:32])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=S(=O)(Cl)CCCCCl
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCCl)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 59) and 4-chloro-butane-1-sulfonyl chloride (Example 254) in an analogous manner as described in Example 177. HR-MS (ES, m/z) calculated for C21H27N5O4SFCI [(M+H)+] 500.1532, observed 500.1529.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:6]=2[N:7]=1.[CH3:20][N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:10][C:9]([C:11]([NH:21][CH3:20])=[O:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1

Procedure:
A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (1.0 eq), HATU (1.5 eq), hydrochloride salt of methylamine (1.5 eq), diisopropylethylamine (3.0 eq) in DMF was stirred for 30 minutes. Reaction mixture was quenched with saturated aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to give 2-chloro-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide. MS (Q1) 297 (M)+
Reaction SMILES: [CH:1]([N:4]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])[C:5](=[O:8])[CH2:6][OH:7])([CH3:3])[CH3:2].Cl[C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.[OH-].[K+]>C(O)(C)C>[CH:1]([N:4]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])[C:5](=[O:8])[CH2:6][O:7][C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)([CH3:3])[CH3:2]
Reactant: Clc1nc2ccccc2o1
Reactant: CCOCCON(C(=O)CO)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCOCCON(C(=O)COc1nc2ccccc2o1)C(C)C
Reaction time: 6 h
Yield: 94 %

Procedure:
First 20.5 g (0.1 mole) of hydroxyacetic acid N-isopropyl-N-(2-ethoxyethoxy)-amide and then 15.4 g (0.1 mole) of 2-chlorobenzoxazole were added dropwise to a solution of 6.2 g (0.11 mole) of potassium hydroxide in 200 ml of isopropanol at 0° to 5° C., and the mixture was then subsequently stirred for 6 hours, without cooling. The solvent was then distilled off in vacuo, the residue was dissolved in 200 ml of toluene and the solution was extracted by shaking once with 100 ml of water. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was subjected to incipient distillation at 60° C. under a high vacuum. 30.3 g (94% of theory) of benzoxazol-2-yl-oxyacetic acid N-isopropyl-N-(2-ethoxy-ethoxy)-amide were obtained in this manner in the form of a light brown oil with a refractive index nD22 of 1.4986.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.[CH:9]([NH2:12])([CH3:11])[CH3:10]>>[CH3:10][CH:9]([N:12]=[C:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1)[CH3:11]
Reactant: CC1CCCC(=O)C1
Reactant: CC(C)N
Product: CC1CCCC(=NC(C)C)C1
Reaction time: 8 h

Procedure:
To a mixture of 112 g. 3-methyl cyclohexanone and 120 g. isopropylamine are added 100 g. Linde Type 3A molecular sieves. The mixture is allowed to stand overnight at room temperature, after which the sieves are removed by filtration and the excess of isopropylamine is removed in vacuo at room temperature. The oil residue is 1-methyl-N-(3-methyl cyclohexylidene)-ethylamine, b.p. 36 to 0.5 mm.