Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])O.[Na+].[Cl:15][C:16]1[C:24]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].C(OCC)(=O)C>O1CCCC1.O>[Cl:15][C:16]1[C:24]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8])=[O:19]
Reactant: Nc1cc(O)ccc1F
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(O)ccc2F)c1Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
2-Chloro-3-(1-cyano-1-methylethyl)benzoic acid (3.0 g, 13.4 mmol) was dissolved in tetrahydrofuran (67 mL), and oxalyl chloride (1.35 mL, 15.8 mmol) and N,N-dimethylformamide (20 μL) were added. The reaction mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure to give 2-chloro-3-(1-cyano-1-methylethyl)benzoyl chloride. To a solution of 3-amino-4-fluorophenol (1.62 g, 12.8 mmol) in tetrahydrofuran (20 ml) was added a suspension of sodium hydrogen carbonate (3.22 g, 38.3 mmol) in water (40 mL), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise at 0° C. a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoyl chloride produced above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added ethyl acetate (100 mL), and the aqueous layer was separated. The organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate/n-hexane to give the title compound (4.13 g, 97%) as a white powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[C:17]([C:18](=[O:21])[C:19]=3[OH:20])=[CH:16][CH:15]=[C:14]([O:22][CH3:23])[CH:13]=4)=[CH:9][C:4]=2[O:3]C1.B(Br)(Br)Br>>[OH:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:21])[C:19]=2[OH:20])=[CH:16][CH:15]=[C:14]([O:22][CH3:23])[CH:13]=3)[CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: COc1ccc2c(=O)c(O)c(-c3ccc4c(c3)OCO4)oc2c1
Agent: BrB(Br)Br
Product: COc1ccc2c(=O)c(O)c(-c3ccc(O)c(O)c3)oc2c1
Yield: 58648816 %

Procedure:
The reaction was conducted according to the same procedure as Example 57 except that 50mg (159 pmol) of the compound obtained in Example 6 instead of the compound obtained in Example 12 and 1.5 molar equivalents of boron tribromide (BBr3) were used. Then the resulting product was separated by preparative TLC to give 28 mg of the title compound in a yield of 60%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]([CH2:16][O:17][N:18]=[C:19]([C:23](=[O:26])[CH2:24][Br:25])[C:20]([OH:22])=O)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[NH2:28][CH:29]1[C:54](=[O:55])[N:31]2[C:32]([C:38]([O:40][CH:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])=[C:33]([CH:36]=[CH2:37])[CH2:34][S:35][C@H:30]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C.CN(C)C=O>[CH2:6]([O:13][C:14]([CH2:16][O:17][N:18]=[C:19]([C:23](=[O:26])[CH2:24][Br:25])[C:20]([NH:28][CH:29]1[C:54](=[O:55])[N:31]2[C:32]([C:38]([O:40][CH:41]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:39])=[C:33]([CH:36]=[CH2:37])[CH2:34][S:35][C@H:30]12)=[O:22])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CON=C(C(=O)O)C(=O)CBr)OCc1ccccc1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccccc3)C(=O)CBr)[C@H]2SC1
Yield: 74.5 %

Procedure:
Vilsmeir reagent prepared from N,N-dimethylformamide (0.67 ml) and phosphorus oxychloride (0.79 ml) was suspended in dry tetrahydrofuran (25 ml). Thereto was added 2-benzyloxycarbonylmethoxyimino-4-bromo-3-oxobutyric acid (2.8 g) at 0° C. with stirring, and the stirring was continued at 0° to 5° C. for an hour to prepare the activated acid solution. This activated acid solution was added at a time to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (2.2 g) and trimethylsilylacetamide (7.0 g) in methylene chloride (30 ml) at -35° C., and the mixture was stirred at -10° to -5° C. for 30 minutes. The reaction mixture was poured into ethyl acetate (200 ml), and the separated organic solution was washed with a saturated aqueous sodium bicarbonate and a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave benzhydryl 7-(2-benzyloxycarbonylmethoxyimino-4-bromo-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylate (2.8 g).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[OH:13])[CH2:8][CH2:7]1)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[OH2:3].[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)([OH:13])[CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:11][CH2:10]2)=[CH:19][CH:18]=1.[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:11][CH2:10]2)([OH:13])[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)CN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 16 h
Yield: 53 %

Procedure:
To a stirred solution of 5.0 g (0.013 mole) of 4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidineacetic acid ethyl ester in 100 mL of 95% ethanol was added a solution of 10.9 g (0.130 mole) of sodium bicarbonate in 150 mL of water and the mixture was heated at reflux for 16 h. The solution was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl ether and water (200 mL each). The layers were separated, and the aqueous layer was further extracted with two 100 mL portions of ethyl ether. The aqueous layer pH was adjusted to 6 with glacial acetic acid, whereupon a solid precipitate began to form. After standing for 16 h, the crystals were collected by filtration, washed with water and recrystallized from 2-propanol to yield 1.7 g (36%) of white solid, mp 198°-200° C.
Reaction SMILES: [OH:1][C@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C@@H:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4].O.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][C@@H:3]([CH3:4])[C@@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[OH:1]
Reactant: COc1cccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1cccc([C@@H](O)[C@H](C)N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl [(1S,2R)-2-hydroxy-2-(3-methoxyphenyl)-1-methylethyl]carbamate (317 mg, 1.13 mmol) in dichloromethane (3 ml) was added water (3 ml), and TFA (5 ml), so that a clear solution has been obtained. The mixture was stirred at r.t. for 1 h, than poured into water (30 ml). The aqueous layer was washed with dichloromethane (30 ml), and made alkaline (pH≈10) by addition of 10 N aqueous NaOH. Brine (20 ml) was added, and the solution was extracted with dichloromethane (3×30 ml). The extracts were dried with Na2SO4, and the solvent was removed under reduced pressure to afford the subtitle compound as colourless oil. Yield 179 mg (88%).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[C:14]2[C:13]([OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][CH:7]=1.O>C(O)(=O)C>[OH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:6]([CH3:5])[CH2:7][NH:8]2
Reactant: Cc1c[nH]c2cccc(O)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1CNc2cccc(O)c21
Temperature: 15 °C
Reaction time: 16.5 h
Yield: 44.4 %

Procedure:
1.35 g of sodium cyanoborohydride are gradually added to a solution of 1.0 g of 3-methyl-1H-indol-4-ol in 35 ml of acetic acid under argon cooled to a temperature of about 15° C. The reaction mixture is allowed to warm up to ambient temperature. After 16.5 hours, the reaction mixture is treated with 15 ml of water, and then concentrated to dryness under reduced pressure. The residue is taken up in 75 ml of ethyl acetate, and then treated with 60 ml of a saturated sodium hydrogen carbonate solution. After stirring for 1 hour and then settling out, the organic phase is separated and the aqueous phase is extracted with 50 ml of ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with an 80/20 v/v cyclohexane/ethyl acetate mixture, with a flow rate of 80 ml/min. 0.45 g of 4-hydroxy-3-methylindoline is thus obtained in the form of a pale yellow solid, the characteristics of which are the following:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]2[C:16](=[O:17])[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[O:12]2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Ni].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[C:11]2[C:16](=[O:17])[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[O:12]2)=[CH:8][CH:9]=1
Reactant: O=C1Nc2ccccc2OC1=Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(C=C2Oc3ccccc3NC2=O)cc1

Procedure:
A catalytic amount of Raney nickel was added portionwise with stirring to a mixture of 2-[(4-nitrophenyl)methylene]-2H-1,4-benzoxazin-3(4H)-one (0.57 g, 0.002 mol) and hydrazine hydrate (1 ml) in ethanol (20 ml). The reaction mixture was refluxed for 3 h, then filtered. The filtrate was evaporated to dryness under reduced pressure. The crude product was purified by re crystallization from ethanol.
Reaction SMILES: [CH:1]1([C:7]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28]CC(O)[CH2:25][CH2:24]1.[Na].[ClH:31]>C1(C)C=CC=CC=1.CCOCC>[ClH:31].[CH:1]1([C:7]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH:11]2[CH2:25][CH2:24][N:23]([CH3:28])[CH2:22][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(O)CC1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCCC1
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN1CCC(OC(=O)C(O)(C#Cc2ccccc2)C2CCCCC2)CC1

Procedure:
This ester was prepared by a method similar to the ones described above from the reaction of ethyl α-cyclohexyl-α-phenylethynyl-glycolate (4.3 g., 0.015 mole), 1-methyl-4-piperidinol (2.3 g., 0.020 mole) and sodium (~0.05 g.) in toluene. The chloroform extract of the basic phase of the reaction mixture, when stripped of volatile components in vacuo, yielded an oil. The oil was dissolved in dry ether and treated with HCl (gas) to give an oily solid. Recrystallization from a chloroform-benzene mixture gave about 0.6 g. (10%) of the desired hydrochloride, m.p. about 198°-200°.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:19])[NH:9][C:10]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:11]2)=[N:6]1)([CH3:4])[CH3:3].Br[C:21]1[C:25](CI)=CN(C(CC)(C)C)N=1>>[C:2]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:19])[NH:9][C:10]3([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH2:11]2)=[N:6]1)([CH2:21][CH3:25])([CH3:4])[CH3:3]
Reactant: CCC(C)(C)n1cc(CI)c(Br)n1
Reactant: CC(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Agent: Cl
Product: CCC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate 3 in Steps 4-8, using 3-bromo-4-(iodomethyl)-1-tert-pentyl-1H-pyrazole. +ESI (M+H) 277.3; 1H NMR (400 MHz, CD3OD, δ): 7.67 (s, 1H), 3.22-3.37 (m, 4H), 2.93 (s, 2H), 1.92 (q, J=7.61 Hz, 2H), 1.88-2.05 (m, 4H), 1.57 (s, 6H), 0.67 (t, J=7.41 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH:5]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)[CH3:2].[H][H]>[Pd].CO>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:18]
Reactant: [H][H]
Reactant: CCN(CC)CC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CC1CCNC1
Reaction time: 20.3 h
Yield: 101.7 %

Procedure:
A mixture of 25.4 g (0.10 mole) of N,N-diethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 200 ml of methyl alcohol, 2 g of palladium on carbon and hydrogen were shaken at a pressure of 51.5 psi. After 20.3 hours, the catalyst was filtered and the filtrate concentrated under reduced pressure. The residue was bulb to bulb distilled giving 15.9 g of N,N-diethyl-3-pyrrolidinemethanamine.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][N:8]=[N:7][C:6]=1[CH3:10])=[O:4].Cl>CO.[OH-].[Na+]>[CH3:10][C:6]1[N:7]=[N:8][S:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1snnc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nnsc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester (1.7 g) is dissolved in methanol (15 mL) and treated with IN sodium hydroxide (16 mL). After stirring at room temperature for 1 hour, the reaction is treated with concentrated hydrochloric acid (1.5 mL) and concentrated under reduced pressure. The resulting turbid aqueous layer is extracted twice with diethyl ether and the pooled organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][C:29]=1[O:37][CH3:38]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(N)=O)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(N)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 64.3 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10.0 mmol), K2CO3 (2.0 g) and 4-(3-bromopropoxy)-3-methoxybenzamide (2.32 g, 8.0 mmol) in acetonitrile (80 ml) was heated at reflux for 5 hours. At the end of the reaction the solvent was evaporated. The residue was extracted into dichloromethane. The inorganic insolubles were filtered off. The dichloromethane was concentrated again. The crude residue was.purified by flash chromatography over a silica gel column (55 g, SiO2 ; eluted with 1% methanol in dichloromethane, 1 l; 2% methanol in dichloromethane, 1 l). The material thus obtained weighed 2.93 g (84%) as white crystals. Recrystallization from hot ethanol (60 ml) gave 2.2 g of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide as white crystals, m.p. =163°-164° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:5]=1.[OH-].[Li+].Cl>O1CCCC1.CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][C:6]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(OC)c(OCCN2CCOCC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)O)cc1OCCN1CCOCC1
Reaction time: 8 h

Procedure:
To stirred solution of the product of step 1 (0.740 g, 2.5 1 mmol) in 1:1 tetrahydrofuran/methanol (20 mL) was added 1 N aqueous lithium hydroxide (5.0 mL, 5.0 mmol). The reaction was allowed to stir overnight and then treated with 1 N aqueous hydrochloric acid (5.0 mL, 5.0 mmol). The solution was concentrated with 1 N aqueous of crude product and sodium chloride as a tacky white solid. This material was used without further purification in the next step.
Reaction SMILES: OC1C=CC(O)=C(C)C=1C.C=O.C(OC)(=O)C(C)=C.O[C:21]1[CH:22]=[C:23]2[C:28](=[C:29](C)[C:30]=1C)[O:27][C:26](C)(C(OC)=O)[CH2:25][CH2:24]2>>[O:27]1[C:28]2[C:23](=[CH:22][CH:21]=[CH:30][CH:29]=2)[CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)C1(C)CCc2cc(O)c(C)c(C)c2O1
Agent: C=C(C)C(=O)OC
Agent: C=O
Agent: Cc1c(O)ccc(O)c1C
Product: c1ccc2c(c1)CCCO2

Procedure:
Into a 30-mL stainless-steel pressure reactor equipped with a stirrer, 1,4-dihydroxy-2,3-dimethylbenzene (0.91 g, 6.6 mmol), an aqueous formalin solution (0.73 g, formaldehyde 37 wt. %, methanol 7 wt. %, and water 56 wt. %), and methyl methacrylate (8.3 g, 83.0 mmol) were placed. The mixture was allowed to react at 180° C. for three hours under stirring, while the reactor was tightly closed. After cooling, the reaction mixture was analyzed, and methyl 6-hydroxy-2,7,8-trimethylchroman-2-carboxylate was found to be formed as a chroman compound. Reaction scores on the basis of 1,4-dihydroxy-2,3-dimethylbenzene were found to be as follows:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][N:7]=[C:6]([O:13][CH3:14])[C:5]=2[N:4]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:14][O:13][C:6]1[C:5]2[N:4]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])[C:10]=2[C:9]([C:11]#[N:12])=[CH:8][N:7]=1
Reactant: COc1ncc(C#N)c2c(Br)cn(COCC[Si](C)(C)C)c12
Reactant: Cc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ncc(C#N)c2c(-c3ccccc3C)cn(COCC[Si](C)(C)C)c12
Temperature: 90 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of 3-bromo-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-4-carbonitrile (1.30 g) in toluene (17 mL) were added 2-dicyclohexyl phosphino-2′,4′,6′-triisopropylbiphenyl (0.486 g), tris(dibenzylideneacetone)dipalladium(0) (0.311 g), (2-methylphenyl)boronic acid (0.693 g) and 2M aqueous sodium carbonate solution (5.10 mL) at room temperature, and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained fraction was treated with activated carbon, and concentrated under reduced pressure to give the title compound (1.20 g).
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]1[C:16]2[O:17][CH2:18][CH2:19][C:15]=2[C:14]2[C:13]3[CH2:12][CH2:11][NH:10][C:9](=[O:20])[C:8]=3[NH:7][C:6]=2[CH:5]=1>C(O)C>[NH2:10][CH2:11][CH2:12][C:13]1[C:14]2[C:6](=[CH:5][C:4]([F:3])=[C:16]3[C:15]=2[CH2:19][CH2:18][O:17]3)[NH:7][C:8]=1[C:9]([OH:20])=[O:1]
Reactant: [OH-]
Reactant: O=C1NCCc2c1[nH]c1cc(F)c3c(c21)CCO3
Agent: [K+]
Solvent: CCO
Product: NCCc1c(C(=O)O)[nH]c2cc(F)c3c(c12)CCO3
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a stirring solution of KOH (214 mg, 3.82 mmol) in ethanol (50%), compound 10 (108 mg, 0.438 mmol) was added. It was refluxed for 6 h and kept overnight at room temperature. The solvent was removed and water was added to the residue thus obtained. It was filtered and acidified with acetic acid. The solid obtained was washed with water. The filtrate was again extracted with ethyl acetate. The organic layer was concentrated to yield the desired compound 11 (55 mg, yield 47.45%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[C:41]([S:45]([NH:48][CH2:49][CH3:50])(=[O:47])=[O:46])=[CH:40][C:36]=1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:34][C:35]1[C:36]([C:37]([N:11]2[CH2:10][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12]2)=[O:38])=[CH:40][C:41]([S:45]([NH:48][CH2:49][CH3:50])(=[O:46])=[O:47])=[C:42]([F:44])[CH:43]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCNS(=O)(=O)c1cc(C(=O)N2CCC(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c(Cl)cc1F
Yield: 44 %

Procedure:
0.103 g (0.23 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole and 0.129 g (0.46 mmol) 2-chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by flash chromatography on a 0-100% gradient of 1N methanolic ammonia in ethyl acetate in ethyl acetate. 0.76 g obtained (44% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.04-8.14 (m, 1H), 7.86-7.89 (d, 1H J=9.83 Hz), 7.72-7.79 (m, 3H), 7.41-7.51 (m, 3. H), 7.21-7.26 (m, 2H), 7.09-7.15 (m, 1H), 5.00-5.11 (m, 1H), 4.03-4.14 (m, 2H), 3.87-3.99 (m, 1H), 3.19-3.38 (m, 2H), 2.96-3.05 (m, 1H), 2.85-2.94 (m, 3H), 2.69-2.80 (m, 4H), 2.51-2.64 (m, 2H), 1.93-2.26 (m, 11H), 1.73-1.88 (m, 2H), 0.94-1.12 (m, 3H). LC/MS m/z (M+H): 710.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]([C:26]([O-:28])=[O:27])[C:16]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([OH:20])[C:17]([O-:19])=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd].[C]>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]([C:26]([OH:28])=[O:27])[C:16]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([OH:20])[C:17]([OH:19])=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(C(C(=O)[O-])C(O)(C(=O)[O-])C2CCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CCC(C(C(=O)O)C(O)(C(=O)O)C2CCCC2)CC1
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of a diastereomeric mixture (330 mg, 0.55 mmol) of dibenzyl 3-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl-2-cyclopentyl-2-hydroxysuccinate in ethanol (10 ml) was added 10% Pd carbon (150 mg) under a nitrogen gas stream. The atmosphere in a reaction vessel for the mixture was replaced five times with nitrogen gas, the reaction vessel was filled with hydrogen gas, and the contents of the reaction vessel were stirred for 24 hr under a hydrogen gas stream. The catalyst was collected by filtration through Celite pad and was washed with ethanol, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (190 mg, yield 83%).