Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:14][CH2:13][CH2:12][S:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(SCCCl)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 55.4 %

Procedure:
4-Mercaptobenzoic acid (65 mmol) and 1-Bromo-2-chloro-ethane (71 mmol) are dissolved in acetone (120 ml) and powdered potassium carbonate (71 mmol) is added. The mixture is warmed up to 40° C. and stirred for 7 hours. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water and dried over sodium sulfate and evaporated. The crude product is suspended in diethylether and the solid filtered of and dried (vacuum). 7.8 g of a white powder with mp. 142-144° C., Rf=0.37 (methylenchlorid/methanol=9/1) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:49]([O:51][CH2:52][CH:53]([O:55][CH2:56][CH3:57])O)[CH3:50].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:50][CH2:49][O:51][CH2:52][CH2:53][O:55][CH2:56][CH3:57])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Reactant: CCOCC(O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (164 mg), 2-ethoxy-(2-ethoxy)ethanol (0.09 mL) and diethyl azodicarboxylate (0.10 mL). The mixture is stirred at room temperature overnight. The reaction mixture is again treated with triphenylphosphine (164 mg), 2-ethoxy-(2-ethoxy)ethanol (0.09 mL) and diethyl azodicarboxylate (0.10 mL). After 4 hours, the reaction mixture is concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with acetone and then by recrystallization from ethyl acetate-heptane to afford 0.18 gm of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:12])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
(S)-(−)-2-(tert-Butoxycarbonylamino)-1-propanol (523 mg, 2.98 mmol, 1.0 equiv.) was dissolved in 45 mL methylene chloride in a 100 mL r.b. flask with a magnetic stir bar. To this clear homogeneous solution, Dess-Martin periodinane (1.523 g, 3.591 mmol, 1.2 equiv.) was added in one portion and the cloudy white reaction mixture was allowed to stir at room temperature for 2 h. Thin-layer chromotography monitored the reaction to completion. The reaction mixture was diluted with 100 mL ethyl acetate. Sodium bisulfite solution (2 M, 20 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was washed with 3×30 mL EtOAc. The combined organic layers were washed with 50 mL 1 M NaOH, followed by saturated NaCl (30 mL) and dried over MgSO4. Filtration and rotary evaporation produced the desired product as a yellow oil (475 mg, 92% yield, Rf=0.63, 1:1 hexanes/ethyl acetate).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH3:7][N:8]1[C:12](C=O)=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=[CH:9]1.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O.O>[CH3:7][N:8]1[C:12]([C:1]([OH:2])=[O:4])=[C:11]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:10]=[CH:9]1
Reactant: O=C([O-])[O-]
Reactant: Cn1cnc(-c2ccccc2)c1C=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1cnc(-c2ccccc2)c1C(=O)O
Reaction time: 24 h
Yield: 68.8 %

Procedure:
Potassium carbonate (3.13 g) was added to 1-methyl-4-phenyl-1H-imidazole-5-carbaldehyde (intermediate 2) (2.33 g) dissolved in acetone (125 mL) and water (25 mL). Once dissolved, potassium permanganate (4.23 g) was added and the mixture stirred for 24 hours. The mixture was filtered through diatomaceous earth and the cake washed with water (2×20 mL). Acetone was evaporated from the filtrate which was extracted with EtOAc (50 mL). The aqueous layer was acidified with acetic acid to pH 5, reduced to half volume and a cream precipitate filtered and dried at 60° C. in vacuo to give the title compound as a cream solid (1.74 g, 69%);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.I[CH:15]([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:15]([CH3:17])[CH3:16])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc2cc(F)cc(OC(C)C)c2n1
Temperature: 70 °C
Yield: 89.6 %

Procedure:
To 6-fluoro-2-methylquinolin-8-ol (1.0 g, 5.6 mmol) in acetone (20 mL) were added 2-iodopropane (1.9 g, 11 mmol) and K2CO3 (2.3 g, 17 mmol). The reaction was heated to 70° C. for 20 hours in a sealed tube and then cooled. Water was added and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure to yield 6-fluoro-8-isopropoxy-2-methylquinoline (1.1 g, 89% yield) as a dark oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[CH2:15][CH:16]([CH3:18])[CH3:17])=O.COC1C=CC(/C=[C:34]2/[C:35]([NH:37][C:38]([S:40]/2)=[NH:39])=[O:36])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:39][C:38]1[S:40]/[C:34](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[CH2:15][CH:16]([CH3:18])[CH3:17])/[C:35](=[O:36])[N:37]=1
Reactant: CC(C)Cc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Cc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 6-formyl-4-isobutyl-quinoline-3-carbonitrile (example 46f), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-isobutyl-quinoline-3-carbonitrile. LC-MS m/e 337 (MH+).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[Cl:32][C:31]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][C:18]=1[N:17]=[C:1]=[S:2]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (2.12 g, 9.1 mmol) was added to a mixture of N-(3-amino-4-chlorobenzyl)-2,2-dimethyl-propionamide (2.00 g, 8.3 mmol) and DCM (60 mL) and stirred at rt for 1.5 h. The mixture was filtered over silica gel. The organic layer was concentrated to give the sub-title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])C.[CH3:16][NH:17][NH2:18]>CCO>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[CH:5]=[C:4]([OH:3])[N:17]([CH3:16])[N:18]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: CNN
Solvent: CCO
Product: Cn1nc(-c2ccccc2F)cc1O
Yield: 76.7 %

Procedure:
To a solution of ethyl-2-fluorobenzoylacetate (4.3 ml, 24 mmol) in EtOH (48 ml) was added methylhydrazine (1.32 ml, 25 mmol) under N2 at RT. The reaction was heated at reflux for 18 h. The mixture was then evaporated, and the off white solid residue taken up in hot EtOAc. The mixture was cooled down, and the white solid not dissolved was collected via filtration and washed with hexane, then dried under reduced pressure to yield 5-(2-fluorophenyl)-2-methyl-2H-pyrazol-3-ol (intermediate XXVIIIa, 3.54 g, 77% yield). M+=193.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[S:33][C:34]([CH:38]=O)=[C:35]([CH3:37])[CH:36]=2)=[CH:4][N:3]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[S:33][C:34]([CH2:38][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[C:35]([CH3:37])[CH:36]=2)=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: COc1cc(-c2csc3c(-c4cc(C)c(C=O)s4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(-c4cc(C)c(CN5CCOCC5)s4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-{4-[4-amino-7-(5-formyl-4-methylthien-2-yl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (70.0 mg, 0.127 mmol) and morpholine (44.2 μL, 0.507 mmol) were reacted according to General Procedure B followed by HPLC purification to give the title compound as a light yellow powder. (3.2 mg, 0.0051 mmol): LCMS (Conditions a): MH−=622, RT=4.73 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.06 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 7.58 (dd, J=8.4, 0.80 Hz, 1H), 7.34 (m, 1H), 7.32 (m, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.20 (s, 1H), 7.12–7.16 (m, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H), 5.69 (br, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.63 (s, 2H), 3.60 (t, J=4.6 Hz, 4H), 2.46 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH:12]2[CH2:17][CH:16]3[CH2:18][CH:14]([C:15]3([CH3:20])[CH3:19])[CH:13]2[CH3:21])[CH2:7][C:6]1=[O:22])(=O)[CH2:2][CH3:3].[Cl-].[CH2:24]([O:27][NH3+:28])[CH:25]=[CH2:26].C([O-])(=O)C.[Na+]>C(O)C>[CH2:24]([O:27][NH:28][C:1](=[C:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH:12]2[CH2:17][CH:16]3[CH2:18][CH:14]([C:15]3([CH3:19])[CH3:20])[CH:13]2[CH3:21])[CH2:7][C:6]1=[O:22])[CH2:2][CH3:3])[CH:25]=[CH2:26]
Reactant: CCC(=O)C1C(=O)CC(C2CC3CC(C2C)C3(C)C)CC1=O
Reactant: C=CCO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: C=CCONC(CC)=C1C(=O)CC(C2CC3CC(C2C)C3(C)C)CC1=O
Yield: 91 %

Procedure:
7.5 parts by weight of 2-propionyl-5-(2,6,6-trimethylbicyclo[3.1.1]-hept-3-yl)-cyclohexane-1,3-dione, 2.9 parts per weight of allyloxyammonium chloride, 2.2 parts by weight of anhydrous sodium acetate and 80 of ethanol were stirred at room temperature for 12 hours, the solvent was distilled off under reduced pressure, the residue was stirred with 120 parts of water and 100 parts of methylene chloride, the organic phase was separated off, the aqueous phase was extracted with 50 parts of methylene chloride, and the combined organic phases were washed with water, dried over sodium sulfate and evaporated down under reduced pressure. 2-(1-allyloxyaminopropylidene)-5-(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)cyclohexane-1,3-dione was obtained in 91% yield as an oil (compound no. 2); nD33 : 1.5317.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([N:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)=[CH:12][C:11]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[N:10]2)=[CH:30][CH:31]=1
Reactant: BrCc1ccccn1
Reactant: CCOC(=O)Nc1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Product: CCOC(=O)N(Cc1ccccn1)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 97 %

Procedure:
2-(4-Chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one (70 mg) and 2-pyridylmethyl bromide were processed as in Example 116 (stirred at 70° C. for 4 hours), whereby the title compound (82 mg, 97.0%) was obtained.
Reaction SMILES: [Mg].[CH2:2]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1>C1COCC1.Cl[Pd]Cl>[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:10]2[CH:9]=[CH:8][C:7]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH:11]=2)=[CH:19][CH:18]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CCCCCc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A Grignard compound is prepared from 1.2 g of magnesium, 50 ml of THF and 11.4 g of 4-pentyl-bromobenzene in 25 ml of THF. When the addition is complete, the mixture is refluxed for a further 1 hour and cooled to 10° and 14 g of 4-trifluoromethoxy-bromobenzene in 25 ml of THF and 0.73 g of PdCl2 (dppf) are added. The cooling is removed, but the reaction mixture should not climb above 20°. The mixture is subsequently stirred at room temperature for 16 hours, poured into 100 ml of saturated NH4Cl solution and stirred for a further 15 minutes, and the organic phase is then worked up. After purification by crystallization, trifluoromethoxy-4-(4-pentylphenyl)benzene having C 67° I is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[C:20]([C:29]4[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1>ClCCl.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[C:20]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1
Reactant: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccc(Br)cc4)c(-c4ccc(F)cc4)c23)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(F)cc4)c23)c1
Temperature: 25 °C

Procedure:
Dissolve 115 mg (0.21 mmol) of 3-{[6-(4-bromophenyl)-5-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino}phenoxy acetic acid methyl ester in 5 ml of dichloromethane and 5 ml of ethyl acetate, and add 22 mg of 10% palladium on activated carbon under argon. Stir the mixture under a hydrogen atmosphere of 3 bar gauge at RT until the starting material has been converted completely. Filter off the catalyst, concentrate the resulting filtrate under reduced pressure and chromatograph the residue on silica gel (eluent: dichloromethane/ethyl acetate 10:1). 27.9 mg (28.3% of theory) of the target compound are obtained as a colourless solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Reactant: OB(O)c1ccncc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccncc2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 1 from (R)-3′-(5-bromo-thiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-4-boronic acid. The title compound (34 mg) was obtained as a pale-yellow solid, m/z 342 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24](O)=[O:25])[CH:17]=3)[O:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:41][O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:11][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24]([NH:41][O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)=[O:25])[CH:17]=3)[O:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Yield: 117673.3 %

Procedure:
A suspension of (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (490 g, 1.30 mmol) in DCM (6.5 ml) was treated with TEA (0.12 ml, 0.90 mmol) and then with EDC (172 mg, 0.900 mmol), HOBt (122 mg, 0.904 mmol) and NH2OTHP (82 mg, 0.72 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (380 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][N:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.[CH3:21][C:22]([O:25][C:26]([NH:28][C@H:29]([CH2:33][CH3:34])[C:30](O)=[O:31])=[O:27])([CH3:24])[CH3:23].CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:20])[C:6]2[C:7]([O:12][C:13]3[N:14]=[CH:15][C:16]([NH:19][C:30]([C@H:29]([NH:28][C:26](=[O:27])[O:25][C:22]([CH3:24])([CH3:23])[CH3:21])[CH2:33][CH3:34])=[O:31])=[CH:17][N:18]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(Oc2ncc(N)cn2)c2c1OCC2(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinamine (Intermediate 33, 220 mg, 0.81 mmol) was dissolved in ethyl acetate (10 mL) and of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (181.1 mg, 0.89 mmol) was added followed by the addition of Et3N (0.35 mL, 2.02 mmol). The resulting solution was cooled down to 5° C. and a solution of T3P 50% w/w in ethyl acetate (0.53 mL, 0.89 mmol) was added drop wise in 15 min. The reaction mixture was stirred for 30 min at 5° C. The reaction was quenched with water (50 mL) and ethyl acetate (50 mL), two phases were separated and the organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 60:40 as eluent affording the title compound (213 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CS(N)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of p-nitrobenzoylchloride (0.925 g, 5.0 mmol) and methanesulfonamide (0.465 g, 4.9 mmol) in dry DCM (10 mL) was cooled to 0° C. To this was added triethylamine (1.48 g, 14.7 mmol) then the mixture was allowed to warm to r.t. and stirred for 12 h. Concentration in vacuo gave the crude title compound, which was used without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[C:6](=[O:14])[C:7]([CH3:13])=[C:8]([CH3:12])[C:9](=O)[CH:10]=1>O.CO>[CH3:13][C:7]1[C:6](=[O:14])[C:5]([CH3:4])=[CH:10][C:9](=[N:2][OH:3])[C:8]=1[CH3:12]
Reactant: NO
Reactant: CC1=CC(=O)C(C)=C(C)C1=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1=CC(=NO)C(C)=C(C)C1=O
Reaction time: 2 h
Yield: 66.9 %

Procedure:
A solution of 7.04 g of hydroxylamine hydrochloride in 30 ml of water was added at room temperature to a solution of 16.9 g of trimethylbenzoquinone [prepared as described in step (a) above] in 150 ml of methanol, and the resulting mixture was stirred for 2 hours, after which it was allowed to stand for 2 days. At the end of this time, the reaction mixture was diluted with 1000 ml of water. The precipitate which separated out was collected by filtration and recrystallized from a mixture of ethyl acetate and hexane, to give 11.2 g of the title compound, melting at 188-190° C.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[C:37]1[C:41]([C:42](Cl)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[C:37]1[C:41]([C:42]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)O[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 633.6 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[CH2:4][O:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CCOCC>[CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:10]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCO)cc2)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Product: CC1(C)OC[C@@H](COc2ccc(CCCOS(C)(=O)=O)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To (3-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-propan-1-ol (12.2 g, 46 mmol) in dry ether (150 ml) is added TEA (12.8 ml, 92 mmol). The mixture is cooled to 0° C. and treated dropwise with methanesulfonyl chloride (5.3 ml, 69 mmol). The reaction mixture is allowed to warm to room temperature and then stirring continued for 3 hours. The resulting mixture is washed with water (2×100 ml), saturated aqueous sodium hydrogencarbonate, brine, dried (MgSO4) and concentrated in vacuo to give Methanesulfonic acid 3-[4-((R)-2,2-dimethyl [1,3]dioxolan-4-ylmethoxy)-phenyl]-propylester as a white solid; 1H NMR (CDCl3): 1.39 (3H, s), 1.43 (3H,$), 2.02 (2H, pent, J=6.9 Hz), 2.63 (2H, tr, J=6.9 Hz), 3.00 (3H, s), 3.90 (2H, m), 4.05 (1H, m), 4.14 (3 h, m), 4.46 (1H, pent, J=6.8 Hz), 6.82 (2H, d, J=7.4 Hz), 7.10 (2H, d, J=7.4 Hz).