Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:37])([Cl:36])[CH2:3][O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23]CC2C=CC(C(F)(F)F)=CC=2)=[O:22])[CH:15]=1.ClC(Cl)(Cl)COC(=O)C1C=CC=CC=1CSC1C=CC=C(CC(O)=O)C=1.[F:64][C:65]([F:76])([F:75])[C:66]1[CH:71]=[CH:70][C:69]([CH:72](O)[CH3:73])=[CH:68][CH:67]=1.C(Cl)Cl>CN(C1C=CN=CC=1)C.CCCCCCC.CCOC(C)=O>[Cl:1][C:2]([Cl:36])([Cl:37])[CH2:3][O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23][CH2:73][CH2:72][C:69]2[CH:68]=[CH:67][C:66]([C:65]([F:64])([F:75])[F:76])=[CH:71][CH:70]=2)=[O:22])[CH:15]=1
Reactant: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Reactant: CC(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCCc1ccc(C(F)(F)F)cc1
Yield: 68 %

Procedure:
The titled compound was prepared according to the method described for 2-[3-(4-trifluoromethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid 2,2,2-trichloro-ethyl ester above from 2-(3-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (168 mg, 0.387 mmol), 1-(4-trifluoromethyl-phenyl)-ethanol (88 mg, 0.465 mmol), EDCxHCl (111 mg, 0.581 mmol), DMAP (4.7 mg, 0.039 mmol) and DCM (4 mL). The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as eluent to yield the titled compound (160 mg, 68%) as an oil; 1H NMR (400 MHz, CDCl3): δ 2.67 (dd, 2H), 3.23 (s, 2H), 4.03 (dd, 2H), 4.27 (s, 2H), 4.67 (s, 2H), 6.74 (br d, 1H), 6.85-6.99 (m, 6H), 7.06 (dd, 1H), 7.13 (dd, 1H), 7.22 (d, 2H), 7.79 (d, 1H); Mass spectrum: M−H+ 604.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([CH:8](C(OCC)=O)[C:9]([O:11]CC)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl>O>[F:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(F)c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: O=C(O)Cc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of diethyl (3-fluoro-2-nitrophenyl)propanedioate (5.50 g, 18.3 mmol) in 40 mL of water was added 40 mL of concentrated hydrochloric acid and the mixture was refluxed for 5 hours. Cooled to room temperature, the mixture was extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated to get crude (3-fluoro-2-nitrophenyl)acetic acid, which was used for next step without purification.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH:21]1[C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[N:18][N:19]=[N:20]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC(c2nnn[nH]2)CC1
Agent: [Pd]
Solvent: CCO
Product: C1CC(c2nnn[nH]2)CCN1
Yield: 94.2 %

Procedure:
A mixture of 4-(1H-Tetrazol-5-yl)-piperidine-1-carboxylic acid benzyl ester (0.6 g, 2.08 mmol) and activated 10 wt. % palladium on carbon (0.065 g) in ethanol (35 mL) was stirred vigorously under 1 atmosphere hydrogen atmosphere for 4 hours. The reaction mixture was then filtered through a microglass filter paper and the solid washed abundantly with methanol and water. The solvent was evaporated in vacuo to yield the 4-(1H-tetrazol-5-yl)-piperidine as a white solid (0.30 g, 94%).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH:10]=[O:11])[CH2:5][CH2:4]1.OS([O-])=O.[Na+].[C-:17]#[N:18].[K+]>O>[OH:11][CH:10]([CH2:9][CH:6]1[CH2:7][CH2:8][N:3]([O:2][CH3:1])[CH2:4][CH2:5]1)[C:17]#[N:18]
Reactant: [C-]#N
Reactant: CON1CCC(CC=O)CC1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CON1CCC(CC(O)C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (1-methoxy-piperidin-4-yl)-acetaldehyde (10 g, 63 mmol) and NaHSO3 (8.6 g, 83 mmol) in 210 ml of water was stirred at room temperature for 30 min. Then, a solution of KCN (6.2 g, 95 mmol) in 50 ml of water was added to the mixture. After the addition, the mixture was stirred at room temperature for another 10 h. The resulting mixture was extracted with CH2Cl2 five times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel. Yield: 2.1 g of 2-hydroxy-3-(1-methoxy-piperidin-4-yl)-propionitrile as a solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:10])=[NH:9].C[O-].[Na+].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])C.[OH-].[K+].Cl>CO.O>[OH:16][C:17]1[C:18]([C:19]([OH:21])=[O:20])=[CH:24][N:10]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[N:9]=1
Reactant: N=C(N)c1ccccn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(-c2ccccn2)nc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To picolinamidine hydrochloride (1-1-g) (112 g, 0.71 mol) in MeOH (1.1 L) was added sodium methoxide (39.4 g, 0.71 mol) and diethyl ethoxymethylenemalonate (142 g, 0.71 mol). The reaction mixture was heated at reflux overnight and then cooled to room temperature. The resulting mixture was filtered and to the filtrate was added potassium hydroxide (71.4 g, 1.37 mol) in water (265 mL). The reaction was heated at reflux for 2 h. The reaction was cooled to room temperature before adding concentrated HCl (180 mL, 2.35 mol) in portions. The reaction was aged for 2 h. The solids were filtered and rinsed with EtOH, Et2O and then hexane to provide the product, 1-1-h, (110 g, 65%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[CH:13]/[CH:14]2[CH2:19][CH2:18][CH:17]=[CH:16][CH2:15]2)/[CH:11]=[O:12])=[CH:6][CH:5]=1.O.[Cl-]>[OH-].[Na+].CO>[OH:12][CH2:11]/[C:10](/[C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)=[CH:13]\[CH:14]1[CH2:19][CH2:18][CH:17]=[CH:16][CH2:15]1
Reactant: O=C/C(=C\C1CC=CCC1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC/C(=C\C1CC=CCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
2 g of sodium borohydride dissolved in a little 10% strength sodium hydroxide solution are added to a solution of 34 g of Z-2-(4-fluorophenyl)-3-(3-cyclohexenyl)-propenal in 200 ml of methanol. After the reaction mixture has been stirred for 18 hours at room temperature, 100 ml of water are added to the solution and the chloride. The organic phase isolated is then dried over sodium sulfate and evaporated down. 34 g (99%) of Z-1-hydroxymethyl-1-(4-fluorophenyl)-2-(3-cyclohexenyl)ethene are obtained.
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.[CH3:8][C:9]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=1[C:11](Cl)=[O:12]>>[CH3:8][C:9]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=1[C:11]([P:1](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:12]
Reactant: Cc1ccc(C)c(C(=O)Cl)c1
Reactant: COP(OC)OC
Product: COP(=O)(OC)C(=O)c1cc(C)ccc1C
Yield: 80 %

Procedure:
Dimethyl 2,5-dimethylbenzoylphosphonate was prepared in 80% yield by adding an equimolar amount of trimethyl phosphite to 2,5-dimethylbenzoyl chloride.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](O)=[O:5].O.[NH4+:14]>O1CCOCC1>[NH2:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([NH2:14])=[O:5]
Reactant: [NH4+]
Reactant: N[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)[C@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.025 g (15 mmol) of (2R)-2-amino-2-phenylethanoate hydrochloride were suspended in 45 ml of dioxane and 45 ml of aqueous ammonium hydrate were added. After 8 hours at room temperature under stirring the solvent was evaporated and the residue redissolved with chloroform and washed with water. The organic layer was concentrated to afford 1.7 g of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]12[CH2:10][CH:6]([O:7][C:8]1=[O:9])[CH:5]([OH:11])[CH:4]([OH:12])[CH2:3]2.[CH2:13]([NH2:16])[CH2:14][CH3:15].C(O)(=O)C>CO.C(Cl)(Cl)Cl>[CH2:13]([NH:16][C:8]([C:2]1([OH:1])[CH2:10][CH:6]([OH:7])[CH:5]([OH:11])[CH:4]([OH:12])[CH2:3]1)=[O:9])[CH2:14][CH3:15]
Reactant: CCCN
Reactant: O=C1OC2CC1(O)CC(O)C2O
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)C1(O)CC(O)C(O)C(O)C1
Yield: 80 %

Procedure:
In a 50 mL round-bottom flask fitted with a stirring bar, reflux condenser, 0.196 g Lactone 2 (1.125 mmol), and propylamine (0.83 ml, 0.6 g, 10.13 mmol) were combined, then glacial acetic acid (0.19 ml, 0.20 g, 3.36 mmol) was added. The solution was warmed to 85° C. in an oil bath for 30 min, at which time TLC(CHCl3:MeOH:NH3OH=100:10:1) indicated complete consumption of the starting lactone. Reaction mixture was purified by flash column with the same solvent as TLC. Product 3 was collected, yielding 206 mg (80% yield). Mp: 132-133° C., Rf 0.03 (CHCl3:MeOH:NH3OH=100:10:1); MS: [M-H]−=232; 1H NMR (300 MHz, DMSO) δ 0.81 (t, J=6.0 Hz, 3H), 1.41 (ddd, J=13.8, 7.5, 6.9 Hz, 2H) 1.66-1.83 (m, 4H), 3.02 (dd, J=6.9, 6.6 Hz, 2H), 3.22 (t, J=6.0 Hz, 1H), 3.75 (ddd, J=13.8, 9.0, 5.7 Hz, 1H), 3.94 (s, 1H), 4.69 (d, J=4.5 Hz, 1H), 4.90 (d, J=5.4 Hz, 1H), 5.19 (d, J=3.6 Hz, 1H), 5.47 (s, 1H), 7.76 (t, J=5.4 Hz, 1H).
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[C:3](=[O:4])[CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>CN(C)C=O.ClCCl>[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:11]([C:9]1[CH:10]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH2:1][CH2:2][C:3]2=[O:4])=[O:13]
Reactant: COCCN
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCNC(=O)c1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a suspension of 1-indanone-6-carboxylic acid (1.76 g) in N,N-dimethylformamide (50 mL) was added carbonyldiimidazole (3.24 g), and the mixture was stirred at room temperature for 1 hour. Thereto was added a solution of 2-methoxyethylamine (3.76 g) in dichloromethane (50 mL) under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and then dissolved in chloroform. The organic layer was washed with aqueous saturated sodium hydrogen carbonate solution, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (20 mL), and then thereto was added 1-normal hydrochloric acid (20 mL), and the mixture was stirred at room temperature for 12 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with isopropyl ether-ethyl acetate (2:1) to give N-(2-methoxyethyl)-3-oxoindan-5-carboxamide [REx(13-1)] (1.87 g) as a brown powder.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][CH:35]([OH:48])[C:36]#[C:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:40][CH:39]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[OH-].[Na+]>CC(C)=O.O>[C:44]([C:41]1[CH:42]=[CH:43][C:38]([C:37]#[C:36][C:35](=[O:48])[C:34]#[C:33][C:30]2[CH:29]=[CH:28][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:32][CH:31]=2)=[CH:39][CH:40]=1)([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)c1ccc(C#CC(O)C#Cc2ccc(C(C)(C)C)cc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(C#CC(=O)C#Cc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
In a nitrogen atmosphere, while a solution obtained by dissolving 27.5 g of Dess-Martin periodinane in 170 ml of (ultra-dehydrated) acetone is being cooled with ice water, a solution obtained by dissolving 19.5 g of (B) 1,5-bis(4-tert-butylphenyl)-penta-1,4-diyn-3-ol in 70 ml of (ultra-dehydrated) acetone is added to the above solution, followed by stirring at room temperature (23° C. to 25° C.) for 3 hours. A solution obtained by dissolving 5 g of sodium hydroxide in 25 ml of water is added to the reaction mixture, and the yellow precipitate is removed by suction filtration, and washed with acetone. The acetone filtrate is concentrated by distillation under reduced pressure, and 300 ml of ethyl acetate is poured into the obtained concentrated liquid to extract the organic substances, and the separated organic layer is washed with water. The concentrated organic layer is purified by being recrystallized sequentially from a mixed solvent of acetone and hexane and then from a mixed solvent of acetone and ethanol, thereby obtaining 16.0 g of (C) 1,5-bis(4-tert-butylphenyl)-penta-1,4-diyn-3-one. The yield of this stage is 82.5%.
Reaction SMILES: ClC1C=C(F)C(N2C(=O)C=C(C)N(C(F)F)C2=O)=CC=1C(O)=O.[Cl:24][C:25]1[CH:36]=[C:35]([F:37])[C:34]([N:38]2[C:43](=[O:44])[C:42](C)=[C:41]([CH3:46])[N:40]([CH:47]([F:49])[F:48])[C:39]2=[O:50])=[CH:33][C:26]=1[C:27]([O:29][CH:30](C)C)=[O:28].ClC1C=C(F)C(N2C(=O)C(F)=C(C)N(C(F)F)C2=O)=CC=1C(OC(C)C)=O.ClC1C=CC(N2C(=O)C=C(C)N(C(F)F)C2=O)=CC=1C(OC(C)C)=O.ClC1C=C(F)C(N2C(=O)C=C(C)N(C(F)(F)C(F)F)C2=O)=CC=1C(OC(C)C)=O>>[Cl:24][C:25]1[CH:36]=[C:35]([F:37])[C:34]([N:38]2[C:43](=[O:44])[CH:42]=[C:41]([CH3:46])[N:40]([CH:47]([F:48])[F:49])[C:39]2=[O:50])=[CH:33][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: Cc1c(C)n(C(F)F)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O
Agent: Cc1c(F)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C(F)F
Agent: Cc1cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C(F)(F)C(F)F
Product: COC(=O)c1cc(-n2c(=O)cc(C)n(C(F)F)c2=O)c(F)cc1Cl

Procedure:
Further representatives of such compounds of formula I are the ethyl, n-propyl, n-butyl, n-hexyl n-octyl, sec.-butyl, 1-methylbutyl, neopentyl, isobutyl, isopentyl, 2-methylbutyl, 1,2-dimethylpropyl, tert.butyl, 1-ethylpropyl, allyl, 2-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl 1-ethyl-2-propenyl, 4-pentenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 3-butenyl, 2-methyl-2-propenyl, 3-butynyl, 2-butynyl, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-pentyloxymethyl, 1-methoxyethyl, 2-methoxyethyl 2-ethoxyethyl, 2-isopropoxyethyl, 2-methoxy-1-methylethyl, 2-n-butyloxyethyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, 1-cyclopropylethyl, 3-tetrahydrofuryl, tetrahydrofurfuryl, 1,3-dioxan-5-yl, 1,3-dioxolan-5-ylmethyl, benzyl and 4-methoxyphenyl esters of 2-chloro-5-[3-difluoromethyl-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid, isopropyl 2-chloro-5-[3-difluoromethyl-3,6-dihydro-4,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoate, isopropyl 2-chloro-5-[3-difluoromethyl-3,6-dihydro-5-fluoro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoate, isopropyl 2-chloro-5-[3-difluoromethyl-3,6-dihydro-4-methyl-2 6-dioxo-1(2H)-pyrimidinyl]-benzoate and isopropyl 2-chloro-5-[3,6-dihydro-4-methyl-3-(1,1,2,2-tetrafluoroethyl)-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:14]2[N:10]([C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:12]3[C:18](=[O:19])[N:17]([CH3:20])[C:16](=[O:21])[N:15]([CH3:22])[C:13]3=2)[CH2:9][CH:8]=1)(=O)=O.[Br-].[Li+].C([Sn](CCCC)(CCCC)[C:38]1[O:39][C:40]([CH3:43])=[CH:41][CH:42]=1)CCC>C1COCC1.CCOCC>[CH3:22][N:15]1[C:13]2=[C:14]3[N:10]([C:11]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[C:12]2[C:18](=[O:19])[N:17]([CH3:20])[C:16]1=[O:21])[CH2:9][CH:8]=[C:7]3[C:38]1[O:39][C:40]([CH3:43])=[CH:41][CH:42]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)o1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(OS(=O)(=O)C(F)(F)F)=CC3
Agent: [Br-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1

Procedure:
1,3-Dimethyl-2,4-dioxo-5-phenyl-2,3,4,7-tetrahydro-1H-pyrimido[4,5-a]pyrrolizin-9-yl trifluoromethanesulfonate (step 4) (100 mg, 0.227 mmol), Cul (4.31 mg, 0.023 mmol), lithium bromide (39.4 mg, 0.453 mmol), tributyl(5-methylfuran-2-yl)stannane (168 mg, 0.453 mmol) in THF (2 ml) and Pd-118 (14.77 mg, 0.023 mmol) were heated to reflux for 10 mins. The reaction mixture was filtered through a glass filter paper and the filtrate concentrated in vacuo. The crude product was dissolved in the minimum amount DCM/EtOAc and loaded onto a 12 g silica cartridge and eluted with 0-80% EtOAc in iso-hexane. The desired product was eluted at 30% EtOAc. The relevant fractions were combined and concentrated to yield a yellow solid. The isolated solid was suspended in Et2O and the solid filtered to yield the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2=[CH:21][CH:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:19]2[CH:18]=[CH:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:25]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[O:16][CH:17]=[CH:18][C:19]=12)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Reactant: O=C(O)c1cccc2occc12
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)c1cccc2occc12

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with benzofuran-4-carboxylic acid (M. A. Eissenstat et al. J. Med. Chem. 1995, 38, 3094-3105).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2N(CC3C=CC(Cl)=CC=3)N=C(S(C(F)(F)F)(=O)=O)C=2CC1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].C1(B(O)O)C=CC=CC=1>C1COCC1.O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=3[C:12]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:13]2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2c(S(=O)(=O)C(F)(F)F)nn(Cc3ccc(Cl)cc3)c2CC1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(Cn2nc(-c3ccccc3)c3c2CCNCC3)cc1
Temperature: 100 °C

Procedure:
1-(4-Chloro-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. To a solution of 0.13 g of 1-(4-chloro-benzyl)-3-trifluoromethanesulfonyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester, prepared as in Example 43, Steps A through C, in 3 mL of THF was added 300 μL of water, 0.11 g of K2CO3, 44.9 mg of phenylboronic acid, and 20.0 mg of PdCl2dppf. The mixture was heated at 100° C. for 18 h. The mixture was filtered through diatomaceous earth and concentrated in vacuo. Chromatography on SiO2 (hexanes to 45% EtOAc/hexanes) afforded 16.1 mg of the desired compound. MS (ESI): exact mass calculated for C25H28ClN3O2, 437.19; found, m/z 438.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:19]=[O:20])[C:13]=2[CH:12]=[CH:11]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH:19]=[O:20])[C:13]=3[CH:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2Cc1ccc(Cl)cc1
Yield: 99.6 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.97 g of 4-chlorobenzyl bromide and 2.00 g of indole-4-carbaldehyde as a starting material to give 3.70 g of 1-(4-chlorobenzyl)indole-4-carbaldehyde as yellow crystals. The yield thereof was found to be 100%.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([C:8](=[O:15])[CH2:9][CH2:10][CH:11]([CH3:14])[CH:12]=[O:13])=[CH:5][CH2:4][CH2:3]1>C1(C)C=CC=CC=1>[CH3:16][C:2]1([CH3:1])[CH2:7][C:6]([C:8](=[O:15])[CH2:9][CH2:10][CH:11]([CH3:14])[CH2:12][OH:13])=[CH:5][CH2:4][CH2:3]1
Reactant: CC(C=O)CCC(=O)C1=CCCC(C)(C)C1
Solvent: Cc1ccccc1
Product: CC(CO)CCC(=O)C1=CCCC(C)(C)C1
Temperature: 100 °C

Procedure:
5-(5,5-dimethylcyclohex-1-en-1-yl)-2-methyl-5-oxopentanal (6.67 g, 0.03 mol.), toluene (20 g, 300 wt. %) and (ethylenediamine)[1,2-bis(diphenylphosphino)ethane]ruthenium (bispivalate) (2.3 mg, 0.003 mmol, 0.01 mol.%) were loaded altogether in a 125 ml autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged to under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 50 bars hydrogen. It was then heated to 100° C. and hydrogen pressure was maintained to 50 bars during all the reaction to afford desired product with 90.0% selectivity. Upon reaction completion (checked by both hydrogen consumption and GC), autoclave was then cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars) and reaction mixture was then transferred to a round-bottomed flask and solvent was removed under vacuum. After flash chromatography, 1-(5,5-dimethylcyclohex-1-en-1-yl)-5-hydroxy-4-methylpentan-1-one was obtained in 85% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:19]=[C:18](Br)[O:17][CH:16]=2)=[O:14])=[CH:8][CH:7]=1)[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:19]=[C:18]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[O:17][CH:16]=2)=[O:14])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2coc(Br)c2)cc1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)c2coc(-c3ccc(O)cc3)c2)cc1
Yield: 38.2 %

Procedure:
A solution of {4-[(5-Bromo-furan-3-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (828 mg, 2.35 mmoles) (8), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (518 mg, 2.35 mmoles), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg) and 2M aqueous cesium carbonate (3.5 ml, 3.5 mmoles) in N,N-dimethylformamide (20 ml) was heated in a microwave reactor at 100° C. for 15 minutes. The solvent was evaporated, and the residue was purified by flash chromatography (gradient elution with 100% cyclohexane to 50% cyclohexane/50% ethyl acetate) to afford (4-{[5-(4-hydroxy-phenyl)-furan-3-carbonyl]-amino}-phenyl)-acetic acid ethyl ester (11) (328 mg). LC/MS System A; Rt=3.35 mins, m/z (ES+)=366 (M+H for C21H19NO5).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:21]=[C:22]([CH:42]=[CH:43][CH:44]=1)[CH2:23][O:24][C:25]1[CH:26]=[C:27]([NH2:41])[CH:28]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=2)[CH:30]=1)#[N:19]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15](=[O:17])[NH:41][C:27]2[CH:28]=[C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=3)[CH:30]=[C:25]([O:24][CH2:23][C:22]3[CH:42]=[CH:43][CH:44]=[C:20]([C:18]#[N:19])[CH:21]=3)[CH:26]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1cccc(COc2cc(N)cc(OCc3cccc(C#N)c3)c2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2cc(OCc3cccc(C#N)c3)cc(OCc3cccc(C#N)c3)c2)CC1
Yield: 62.5 %

Procedure:
Following the procedure of Example 107(e) trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid 0.41 g (1.68 mmol) and [3,5-Bis-(3-cyano-benzyloxy)-phenyl]-amine (0.6 g, 1.68 mmol) were used to afford 0.61 g of the required product. Percentage purity (LCMS): 79.8%, (M−1)=580.0-1.