Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4]OC.Cl.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[CH3:1][O:2][CH2:3][CH2:4][NH:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:25])[F:26])=[CH:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COCC(OC)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
A solution of methoxyacetaldehyde dimetylacetal (0.162 mL, 1.26 mmol) in 0.5 M HCl aq. (2.52 mL, 1.26 mmol) was heated to 50° C. and stirred under nitrogen for 1 h. The reaction mixture was allowed to cool to room temperature and extracted with CH2Cl2 (10 mL). The organic extract was separated by hydrophobic frit and dried by standing over molecular sieves for 2 h. To this solution was added 4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.3 g, 1.26 mmol), then after 20 minutes sodium triacetoxyborohydride (0.375 g, 1.77 mmol) and acetic acid (0.072 mL, 1.26 mmol) were added. The resultant mixture was stirred at room temperature under nitrogen for 18 h. The reaction was quenched by cautious addition of sat. NaHCO3 aq. (30 mL) and extracted into CH2Cl2 (2×30 mL). The organic extract was passed through a hydrophobic frit and the solvents removed in vacuo. Purification by Biotage™ chromatography eluting with 19:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (0.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:47][N:48]([CH3:61])[C:49](=[O:60])[C@H:50]([NH:58][CH3:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@@H:10]([C:11](=[O:12])[N:58]([C@@H:50]([C:49](=[O:60])[N:48]([CH3:47])[CH3:61])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH3:59])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To a solution of (2R)-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (8.78 g, 26.6 mmol) in dichloromethane (30 ml) were added 1-hydroxy-7-azabenzotriazole (3.62 g, 26.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.54 mg, 28.9 mmol) and the mixture was stirred for 30 min. Then (2R)-N,N-dimethyl-2-methylamino-3-phenylpropionamide (4.58 g, 22.2 mmol) in dichloromethane (15 ml) and diisopropylethylamine (4.94 ml, 28.9 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was washed with water (20 ml), aqueous sodium bicarbonate (20 ml), water (2×20 ml), brine (20 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (400 g) with ethyl acetatelheptane 1:4 to give 6.64 g of N-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:30])[CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37]C(N(C)C)N(C)C)(C)(C)C.CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:30])[C:19]([C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:33][OH:37])=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1cc(CCNC(=O)Cc2ccc3c(c2)CCCC3)ccc1OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
8.8 g (13.6 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide, 8.9 g (51.1 mmol) of t-butoxybis (dimethylamino)methane and 100 ml of N,N-dimethylformamide were mixed and stirred at 100° C. for 6 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. To the residue, 50 ml of 5% hydrochloric acid and 100 ml of tetrahydrofuran were added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=2:1) and dried to give 4.20 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[C:18]([F:38])=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[C:18]([F:38])=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1c(F)cc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(F)cc2c(c1CCC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A solution of tert-butyl (Z)-4-(2-{2-[(1H-indazol-3-yl)methylene]-5-fluoro-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0231 g, 0.0443 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-5-fluoro-6-methoxy-7-[2-(piperidin-4-yl)ethyl]benzofuran-3(2H)-one (0.0152 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH3:27])[C:9]([CH2:18][CH:19]([OH:26])[CH2:20][C:21]([O:23]CC)=[O:22])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].CO>O1CCCC1>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH3:27])[C:9]([CH2:18][CH:19]([OH:26])[CH2:20][C:21]([OH:23])=[O:22])=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)Cc1c(C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1CC(O)CC(=O)O
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoate (52 mg) in tetrahydrofuran (1 ml) was added 1N sodium hydroxide (0.27 ml), followed by methanol (1 ml). After standing at 20° C. overnight, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated to give 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoic acid (45 mg) as an yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:17]Br.S(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: N#Cc1ccc(Oc2cccnc2N)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2cc(Br)cnc2N)cc1
Temperature: 0 °C
Yield: 66.3 %

Procedure:
Placed 4-(2-aminopyridin-3-yloxy)benzonitrile (13.95 g, 66.05 mmol) in acetic acid (50 mL) and cooled to 0° C. Slowly added bromine (4.229 mL, 82.56 mmol) and stirred for an hour. The reaction mixture was poured onto saturated sodium bisulfite and ice. Extracted with dichloromethane three times, washed with 2N NaOH, water, brine, dried, and concentrated. Purified by MPLC eluting with 3:2 hexane:ethyl acetate to afford the title compound (12.7 g, 66.28% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([NH:15]C(=O)C(Cl)(Cl)Cl)[C:12]2[C:7](=[C:8]([CH2:32][CH2:33][CH3:34])[C:9]3[O:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][C:22](=[O:31])[C:10]=3[CH:11]=2)[N:6]=1)=[O:4].N>S(=O)(=O)(O)O>[NH2:15][C:13]1[C:12]2[C:7](=[C:8]([CH2:32][CH2:33][CH3:34])[C:9]3[O:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][C:22](=[O:31])[C:10]=3[CH:11]=2)[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=1
Reactant: CCCc1c2nc(C(=O)OC)cc(NC(=O)C(Cl)(Cl)Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Agent: N
Agent: O=S(=O)(O)O
Product: CCCc1c2nc(C(=O)OC)cc(N)c2cc2c(=O)cc(C(=O)OCC)oc12
Reaction time: 0.5 h

Procedure:
The product of step (a) (1.0 g) was dissolved in concentrated sulphuric acid (1 ml) and stirred vigorously for 0.5 hours. The deep rep solution was then poured into iced aqueous ammonia solution (100 ml), and the precipitate filtered to give the title compound, 0.5 g, as an orange powder, mp 265°-270° C. (decomposes).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(NC(C)C)(C)C.Cl.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:30]#[N:31])[C:24]=2[CH2:23][CH2:22]1.[N:32]1([C:38]2[N:39]=[C:40]([CH2:45][C:46]([O-])=[O:47])[NH:41][C:42](=[O:44])[CH:43]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[Na+]>CN(C)C=O>[N:32]1([C:38]2[N:39]=[C:40]([CH2:45][C:46]([N:21]3[C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:30]#[N:31])[C:24]=4[CH2:23][CH2:22]3)=[O:47])[NH:41][C:42](=[O:44])[CH:43]=2)[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: N#Cc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: N#Cc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.3 %

Procedure:
242 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, 371 mg of N,N-diisopropylamine and 210 mg of 2,3-dihydro-1H-indole-4-carbonitrile hydrochloride are added to a solution of 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, obtained according to example 1c, step 2c, in 3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 72 hours and then concentrated under reduced pressure. The residue is taken up with 100 ml of water and 20 ml of ethyl acetate, and then stirred at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and petroleum ether. The solid obtained is dried with suction, and then dried under reduced pressure at 40° C. 190 mg of 1-{[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}-2,3-dihydro-1H-indole-4-carbonitrile are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1)([O-:10])=[O:9].O>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CN1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Yield: 50 %

Procedure:
Monomethylpiperazine (15 mL) and tetrahydrofuran (60 mL) were placed in a 200 mL eggplant shaped flask, and a solution of 4-nitrobenzylchloride (8.58 g, 50 mmol) in tetrahydrofuran was added dropwise to the mixture at room temperature while stirring. After finishing the instillation, the mixture was stirred at room temperature for 24 hours. The reaction mixture was mixed with distilled water, and the precipitated solids were collected by filtration and dried under reduced pressure to obtain the title compound (5.9 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[C:3](C2OC(C)(C)C(C)(C)O2)=[CH:4][C:5]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)(=[O:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.Br[C:33]1[C:34]([CH3:41])=[CH:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:33]1[C:34]([CH3:41])=[CH:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=1
Reactant: Cc1cc(C#N)ncc1Br
Reactant: CC1(C)OC(c2cc(S(=O)(=O)N3CCCCc4ccccc43)c(O)cc2Cl)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C#N)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Temperature: 100 °C
Yield: 73.4 %

Procedure:
5-Chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenol (153.0 mg, 0.33 mmol), 5-bromo-4-methyl-pyridine-2-carbonitrile (60 mg, 0.30 mmol), Pd(Ph3P)4 (38 mg, 0.03 mmol) and K2CO3 (138 mg, 1.0 mmol) in a mixture of dioxane (4 mL) and water (0.4 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and then heated at 100° C. for 16 hrs. The mixture was then partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine (2×10 mL) and dried over MgSO4. After filtration and concentration, the material was purified by TLC plates eluting with ethyl acetate in hexanes (1/3) to give 5-[2-chloro-4-hydroxy-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-4-methyl-pyridine-2-carbonitrile 8-1 as a white solid (100 mg). MS: 453.9 (M+H)+; tR=8.37 min (method 2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH2:19]([C@H:21]1[CH2:26][CH2:25][C@H:24](O)[CH2:23][CH2:22]1)[CH3:20].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C>[CH2:19]([C@@H:21]1[CH2:26][CH2:25][C@H:24]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CC[C@H]1CC[C@H](O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reaction time: 0.08 h
Yield: 88.2 %

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (0.3594 g, 0.001477 mol) was added to a capped 40 mL vial. trans-4-Ethylcyclohexanol (0.227 g, 0.00177 mol) was added, followed by tetrahydrofuran (6.00 mL, 0.0740 mol). Triphenylphosphine polymer-bound (1.28 g, 0.00236 mol) was added and the mixture was stirred for 5 minutes. Diisopropyl azodicarboxylate (0.465 mL, 0.00236 mol) was added and the mixture was stirred for 48 hours at room temperature. The mixture was diluted in ethyl acetate, filtered through CELITE™, concentrated under vacuum and purified by flash chromatography (0-20% EtOAc in methylene chloride) to give 0.4603 g of the title compound (88% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]4)[C:6]=2[CH:24]=1.Cl.Cl.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][C@@H:36]([N:38]2[CH2:43][CH2:42][C@H:41]([OH:44])[C@@H:40]([CH3:45])[CH2:39]2)[CH3:37])[CH2:31][CH2:30]1>>[OH:44][C@H:41]1[CH2:42][CH2:43][N:38]([C@@H:36]([CH3:37])[CH2:35][N:32]2[CH2:31][CH2:30][CH:29]([NH:28][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:7]3[C:6]5[CH:24]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=5[O:9][CH:8]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:34][CH2:33]2)[CH2:39][C@@H:40]1[CH3:45]
Reactant: O=C(O)c1cc2c(OCc3coc4ccc(F)cc34)cccc2[nH]1
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCc5coc6ccc(F)cc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 113 (see example 60) and amine 56.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[C:5]([OH:10])=[C:4]([CH2:11]O)[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>Cl.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][C:18]2[CH:19]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=2[OH:20])[C:5]([OH:10])=[C:6]([CH2:8][C:18]2[CH:19]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=2[OH:20])[CH:7]=1
Reactant: Oc1ccc(F)cc1
Reactant: OCc1cc(Cl)cc(CO)c1O
Agent: Cl
Solvent: c1ccccc1
Product: Oc1ccc(F)cc1Cc1cc(Cl)cc(Cc2cc(F)ccc2O)c1O

Procedure:
A mixture of 4-chloro-2,6-bis(hydroxymethyl)phenol (4.8 g), 4-fluorophenol (16.0 g), benzene (25 ml) and hydrochloric acid (5 drops) was heated on a boiling water bath until all the benzene had evaporated. On cooling the mixture deposited colourless crystals of 4-chloro-2,6-bis(5-fluoro-2-hydroxybenzyl)phenol (11.9 g), mp 228° C.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[C:17]1=[O:22]>ClCCCl>[C:1](=[N:14][CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[C:17]1=[O:22])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CN1CCC(N)C1=O
Solvent: ClCCCl
Product: CN1CCC(N=C(c2ccccc2)c2ccccc2)C1=O

Procedure:
Benzophenone imine [CAS: 1013-88-3] (16.67 g, 91.98 mmol) was added dropwise to a solution of 3-amino-1-methylpyrrolidine-2-one [CAS 119329-48-5] (10 g, 87.60 mmol) in DCE (100 mL) under N2 and the reaction was heated at reflux for 18 hours. The solvent was evaporated to afford an amber oil. This was purified using flash silica in a large sinter funnel, eluting with 4:1 to 3:7 i-hexane:EtOAc. An incomplete separation was achieved. 3-(Benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D1) was isolated (25 g) with approximately 11% of an impurity present, but was used in the next step without further purification;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Product: COC(=O)c1c(O)c2cc(-c3ccc(OC)cc3)ccc2sc1=O

Procedure:
4-Hydroxy-6-(4-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 4-methoxy-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.521 (s, 1H), 7.803-7.352 (m, 5H), 7.001 (s, 1H), 4.022 (s, 3H), 3.864 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH:15]([Si](C)(C)C)[CH2:14][CH2:13][CH:12]1[Si](C)(C)C>C(#N)C>[CH3:10][N:11]1[CH:15]2[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=3)[CH2:9][CH:12]1[CH2:13][CH2:14]2
Reactant: CN1C([Si](C)(C)C)CCC1[Si](C)(C)C
Reactant: C=Cc1ccc(Cl)nc1
Solvent: CC#N
Product: CN1C2CCC1C(c1ccc(Cl)nc1)C2
Reaction time: 2.25 h
Yield: 80 %

Procedure:
To a acetonitrile solution containing 3 gms of Ag(1)F. 1.2 gms of dipolarophile (6-chloro-3-vinyl pyridine) was added to 2 gms of N-methyl-2,5-di(trimethyl silyl) pyrrolidine at 25° C. After stirring the reaction mixture for 2 to 2.5 hours, the reaction mixture was filtered through a plug of celite. The solvent was evaporated to give N-methyl Epibatidine in 80% yield which was further purified by column chromatography. Hydrogenation of N-methyl Epibatidine with pd/c for 22 hours gave 70% yield of Epibatidine.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])[C:3]#[CH:4].C[O:14][C:15]([CH3:17])=[CH2:16]>>[CH3:1][C:2]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH:4]=[CH:16][C:15](=[O:14])[CH3:17]
Reactant: C=C(C)OC
Reactant: C#CC(C)(O)CCC=C(C)CC
Product: CCC(C)=CCCC(C)=CC=CC(C)=O

Procedure:
The acid-catalysed reaction of 3,7-dimethyl-non-1-yn-6-en-3-ol with isopropenyl methyl ether and subsequent base-catalysed isomerisation of the resulting β-keto-allene [see G. Saucy, R. Marbet, Helv. 50, 1158 (1967)] yielded in good yield 6,10-dimethyl-dodeca-3,5,9-trien-2-one which was cyclised in a known manner [see H. Rouve, M. Stoll, Helv. 30, 2216 (1947)] with 85% phosphoric acid to give 12/13-methyl-α-ionone. Subsequent reduction with lithium aluminium hydride gave 12/13-methyl-α-ionol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][C@@H:12]([CH3:14])[NH:11][C@@H:10]([CH3:15])[CH2:9]2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:25](Cl)(=[O:27])[CH3:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:8]2[CH2:13][C@@H:12]([CH3:14])[N:11]([C:25](=[O:27])[CH3:26])[C@@H:10]([CH3:15])[CH2:9]2)[CH:7]=1
Reactant: C[C@@H]1CN(c2cc(Cl)ncn2)C[C@H](C)N1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1[C@H](C)CN(c2cc(Cl)ncn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a solution of 4-chloro-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyrimidine(1, 10.29 g, 45.4 mmol) and DIEA (8.80 g, 68.1 mmol. 1.50 equiv.) in 100 ml DCM was added acetyl chloride (4.03 ml, 56.7 mmol, 1.25 equiv.) at room temperature portionwise over 10 min. The reaction was stirred at room temperature for another 30 min. Aqueous NaHCO3 was added to the reaction and the organic layer was washed with NahCO3 (100 ml×2) followed by saturated aqueous NaCl solution. The organic layer was dried over Organic layer was dried over NacSO4. Removal of solvent left a yellow oil. This oily material was triturated in diethyl ether to afford a white solid. The solid was collected by filtration and the washed with diethyl ether again. The solid was dried under vacuum and was weighted at 11.95 g. The yield is 98.2%. LC/MS (M+1=269.1).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:24])=[O:11])[CH2:2]1.[CH3:25][O:26][C:27]([C:29]1[CH:30]=[C:31](OB(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[S:16][C:12]([C:10]([NH:9][CH2:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][N:1]([C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:27]([O:26][CH3:25])=[O:28])[CH2:2]3)=[O:11])=[C:13]([CH3:24])[N:14]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCCNC1
Product: COC(=O)c1cccc(N2CCCCC(CNC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 46 %

Procedure:
Using N-(perhydroazepin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (200 mg, 0.550 mmol) and 3-(methoxycarbonyl)phenylboric acid (198 mg, 1.10 mmol), the same procedure was followed as in Example 2 to give 126 mg (46%) of the desired compound as a colorless powder.