Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32](=[O:52])[CH2:33][C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)[CH3:30]>>[CH2:29]([O:31][C:32](=[O:52])[CH2:33][C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=4)=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)[CH3:30]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-methyl-3-(3-trifluoromethyl-phenyl)-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[NH:5][CH2:6][CH3:7].C(O[C:16](=[O:18])[CH3:17])(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[N:5]([CH2:6][CH3:7])[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1ccc(F)c(Cl)c1
Solvent: CC(=O)O
Product: CCN(C(C)=O)c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84461.5 %

Procedure:
A solution of 3-chloro-N-ethyl-4-fluoroaniline (97.4 g, 0.56 mmol) in glacial acetic acid (225 ml) is treated at 5° with acetic anhydride (105 ml, 1.12 mol). The solution is stirred for one hour, then poured on to ice/water (250 ml) and extracted with ethyl acetate (2×200 ml). The combined phases are washed in succession with water (100 ml), 2N sodium hydroxide solution (100 ml), saturated sodium bicarbonate solution (100 ml), water (10 ml) and 10 percent sodium chloride solution (100 ml). The solution is dried over magnesium sulfate and evaporated. The residue is recrystallized from n-hexane. There are obtained 102 g (84.2%) of 3'-chloro-N-ethyl-4'-fluoroacetanilide.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4](=O)[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:8]2.OCC([NH3+])(CO)CO>>[CH2:16]([C:9]1([CH2:14][CH3:15])[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([CH2:4][C:3]([OH:19])=[O:2])[CH:6]=2)[CH2:10]1)[CH3:17]
Reactant: CCC1(CC)Cc2ccc(C(=O)C(=O)OC)cc2C1
Agent: [NH3+]C(CO)(CO)CO
Product: CCC1(CC)Cc2ccc(CC(=O)O)cc2C1

Procedure:
2,2-diethyl-α-oxo-5-indanacetic acid methyl ester is reduced in a manner analogous to that described in Example 4. The (1,3-dihydroxy-2-hydroxymethyl-2-propyl)ammonium salt of the title compound has an M.P. of 116°-119°.
Reaction SMILES: FC(F)(F)C1C=CC(CCBr)=CC=1.C(C1CCC(C2CCC(=O)CC2)CC1)CCCC.[NH4+].[Cl-].[F:34][C:35]([F:63])([F:62])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]2(O)[CH2:49][CH2:48][CH:47]([CH:50]3[CH2:55][CH2:54][CH:53]([CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.C(OCC)C>[F:34][C:35]([F:62])([F:63])[C:36]1[CH:37]=[CH:38][C:39]([CH2:42][CH2:43][C:44]2[CH2:49][CH2:48][CH:47]([CH:50]3[CH2:55][CH2:54][CH:53]([CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH2:52][CH2:51]3)[CH2:46][CH:45]=2)=[CH:40][CH:41]=1
Reactant: CCCCCC1CCC(C2CCC(O)(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Agent: CCCCCC1CCC(C2CCC(=O)CC2)CC1
Agent: FC(F)(F)c1ccc(CCBr)cc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(C2CC=C(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
A mixture of dry Mg (0.77 g, 0.032 mol), 2-(4-tri-fluoromethylphenyl)ethyl bromide (8.0 g, 0.032 mol) obtained at the second step and diethyl ether (40 ml) was heated at 60° C. for one hour in a sealed tube reactor to obtain a gray, uniform solution, followed by adding this solution to a diethyl ether (30 ml) solution of 4-(4-pentylcyclohexyl)cyclohexanone (7.9 g, 0.032 mol), stirring the mixture at room temperature for 3 hours, feeding the resulting reaction substance into a saturated aqueous solution of NH4Cl, twice extracting with ethyl acetate (50 ml), washing the resulting organic layer, with an aqueous solution of NaCl, drying over anhydrous MgSO4, removing anhydrous MgSO4, distilling off the solvent under reduced pressure, to obtain pale yellow, oily 1-(2-(4-trifluoromethylphenyl)ethyl)-4-(4-pentylcyclohexyl)cyclohexanol (11.4 g), adding thereto toluene (50 ml) and Amberlyst (0.7 g), heating the mixture under reflux for one hour, while removing water formed by the reaction, allowing the resulting substance to cool, feeding it to a saturated aqueous solution of NH4Cl (100 ml), twice washing the resulting separated organic layer with water, drying over anhydrous magnesium sulfate, filtering off the anhydrous MgSO4, distilling off the solvent under reduced pressure, subjecting the resulting residue to column chromatography (silica gel, eluent: heptane) and twice recrystallizing from ethanol (20 ml), to obtain 1-(2-(4-trifluoromethylphenyl)ethyl)-4-(4-pentylcyclohexyl)cyclohexene (4.1 g). Yield: 32%.
Reaction SMILES: [C:1]([O:4][C:5]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].[CH2:21]([NH:25][OH:26])[CH:22]([CH3:24])[CH3:23]>CO.Cl>[C:1]([O:4][C:5]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:8]([CH:9]=[N+:25]([CH2:21][CH:22]([CH3:24])[CH3:23])[O-:26])=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(C)CNO
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(=O)Oc1c(C(C)(C)C)cc(C=[N+]([O-])CC(C)C)cc1C(C)(C)C
Yield: 52.3 %

Procedure:
To a solution of 4-acetoxy-3,5-di-tert-butylbenzaldehyde (17.0 g, 0.0615 mol) in methanol (250 mL) was added isobutylhydroxylamine (5.36 g, 0.0609 mol) and concentrated hydrochloric acid (10 drops). Using a Dean-Stark trap, the resulting solution was refluxed until no more aldehyde was detected by TLC (Rf=0.23 for product and 0.84 for starting material using 3:1 hexanes/EtOAc) The solvent was removed in vacuo and the residue was a red oil which when triturated with hexanes it turned into solid. The solid was separated and washed completely with hexanes. The titled compound was isolated in 52.3% yield as a white solid, m.p. 176.8–180.4° C.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:8]=[C:9](N)[CH:10]=[N:11][CH:12]=1.[BrH:16]>O.C(Cl)Cl.[Cu]Br>[Br:16][C:9]1[CH:10]=[N:11][CH:12]=[C:7]([C:6]([F:15])([F:14])[F:5])[CH:8]=1
Reactant: Nc1cncc(C(F)(F)F)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1cncc(Br)c1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium nitrite (402 mg, 5.83 mmol) in water (6.8 mL) was added slowly to a suspension of 5-(trifluoromethyl)pyridin-3-amine (947 mg, 5.55 mmol) in hydrogen bromide (48% aqueous solution, 1.57 mL) in ice-water bath. After being stirred for 10 min, the resulting orange diazo solution was directly but slowly transferred to a stirring mixture of copper(I) bromide (876 mg, 6.11 mmol) and hydrogen bromide (48% aqueous solution, 0.38 mL). The resulting brown mixture was heated at 60° C. for 1 h. After cooling to room temperature, the mixture was diluted with methylene chloride, washed with 50% NaOH (until pH=11), and water. The aqueous layer was back extracted with methylene chloride. The combined organic extracts were carefully concentrated under vacuum to provide crude product without purification.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li]CCCC.CON(C)[C:20]([C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:21]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]#[C:11][C:20]([C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:21])([CH3:5])([CH3:6])[CH3:7]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CON(C)C(=O)c1oc(-c2ccccc2)nc1-c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC#CC(=O)c1oc(-c2ccccc2)nc1-c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A −15° C. solution of N-BOC propargyl amine (641 mg, 4.13 mmole, 3.5 eq) in dry THF (12 ml) was treated dropwise with a 1.6M n-BuLi in hexanes solution (5.16 ml, 8.3 mmole, 7.0 eq) and the resulting pale yellow dianion solution stirred at −15° C. for 30 minutes under nitrogen. A dry THF solution (3 ml) of the above-prepared 2,4-Diphenyl-oxazole-5-carboxylic acid methoxy-methyl-amide (365 mg, 1.18 mmole, 1.0 eq) was added dropwise to the dianion solution at −15° C. and the mixture stirred at 0° C. for 2 hours under nitrogen. The mixture was quenched by adding a solution of 2M NaH2PO4 (5 ml), then warmed to room temperature and extracted with ethyl acetate. The organic phase was washed with water and brine then dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a crude brown oil. The crude oil without purification was used immediately in next step.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20]([CH2:22]P(OC)(OC)=O)=[O:21]>O>[CH3:18][O:19][C:20](=[O:21])/[CH:22]=[CH:1]/[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)/C=C/c1ccc(C(=O)O)cc1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 107.6 %

Procedure:
4-Formylbenzoic acid (20 g, 0.133 mol) and K2CO3 (55 g, 0.398 mol) were added to water (350 mL) and cooled to 0-5° C. Trimethyl phosphonoacetate (26 mL, 0.160 mol) was charged dropwise maintaining the reaction temperature below 15° C. The reaction was then warmed and stirred at RT for 1.5 h before acidifying to pH˜1. The resulting precipitate was filtered and dried in vacuo to afford the title product as a pale yellow solid (29.5 g, quant). 1H NMR (300 MHz, d6-DMSO) δ: 7.89-7.52 (5H, m), 6.59 (1H, d, J=16.2 Hz), 3.7 (3H, s).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([O:15][C:16]2[CH:39]=[CH:38][C:19]([C:20]([C:22]3[CH:23]=[C:24]([CH2:31][CH2:32][CH2:33][C:34]([O:36]C)=[O:35])[N:25]4[C:30]=3[CH:29]=[CH:28][CH:27]=[CH:26]4)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([C:22]3[CH:23]=[C:24]([CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[N:25]4[C:30]=3[CH:29]=[CH:28][CH:27]=[CH:26]4)=[O:21])=[CH:38][CH:39]=2)[CH2:12][CH2:13][CH3:14])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCC[C@H](Oc1ccc(C(=O)c2cc(CCCC(=O)OC)n3ccccc23)cc1)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC[C@H](Oc1ccc(C(=O)c2cc(CCCC(=O)O)n3ccccc23)cc1)c1ccc(CC(C)C)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 50.2 %

Procedure:
To a solution of methyl 4-[1-[4-[1-(S)-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyrate (182 mg) in ethanol (4 ml) was added 1N aqueous solution of sodium hydroxide (0.6 ml). The mixture was stirred at 50° C. for 40 minutes, and then poured into a mixture of ethyl acetate and diluted hydrochloric acid. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was crystallized with diisopropyl ether to give 4-[l-[4-[l-(S)-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyric acid as white powder (89 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][C@H:9]([NH2:11])[CH2:8][CH2:7][N:6]1[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4].[OH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](O)=[O:31]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][C@H:9]([NH:11][C:30]([C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]=2[OH:19])=[O:31])[CH2:8][CH2:7][N:6]1[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: COC(=O)[C@@H]1C[C@H](N)CCN1CC1CCCCC1
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CCN1CC1CCCCC1

Procedure:
(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylic acid methyl ester was prepared from (2S,4R)-4-amino-1-cyclohexylmethyl-piperidine-2-carboxylic acid methyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C25H33N2O4 [(M+H)+] 425, obsd. 425.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[NH2:5][C:6]1[CH:26]=[C:25]([Cl:27])[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:16])(=[O:15])[CH2:14][C:8]=2[CH:7]=1.O>C(O)=O>[Cl:27][C:25]1[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:15])(=[O:16])[CH2:14][C:8]=2[CH:7]=[C:6]([NH:5][CH:1]=[O:2])[CH:26]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O

Procedure:
Sodium formate (0.308 g, 4.58 mmol) was added to a solution of compound of Example 2 (0.8 g, 2.26 mmol) in formic acid 85% (8 mL) and refluxed for 2 h. The reaction mixture was diluted using water (20 mL) and the solid obtained was filtered, washed with water and dried. The product was purified by crystalisation using DMF/methanol to obtain the title compound. Yield: 0.78 g, (91%); 1H NMR (DMSO-d6, 300 MHz): δ 2.64 (s, 3H, CH3), 5.31 (s, 2H, CH2), 7.70 (s, 1H, Ar), 7.87 (s, 1H, Ar), 7.93 (s, 1H, Ar), 8.08 (s, 1H, Ar), 8.31 (s, 1H, CHO), 10.57 (s, 1H, NH); MS: m/e (ES−) 380 (M−1);
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=O)[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:12][C:11](=[N:20][OH:21])[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1=NO
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 60.2 %

Procedure:
A solution of 24.7 g (0.1 mole) of 1-benzyl-3-ethoxycarbonyl-4-pyrrolidone in 135 ml of ethanol was added dropwise at room temperature to a solution of 34.7 g (0.5 mole) of hydroxylamine hydrochloride dissolved in 135 ml of water, and then 28.1 g (0.265 mole) of sodium carbonate were added to the mixture. The mixture was then stirred at room temperature for 6.5 hours, after which it was extracted with 300 ml of chloroform. The chloroform extract was washed with water and dried over anhydrous sodium sulfate. It was then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 2:1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 15.8 g of 1-benzyl-3-ethoxycarbonyl-4-hydroxyiminopyrrolidine as a brown oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)=[CH:27][CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)=[CH:29][CH:30]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2-c1ccc(OCCn2ccnc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ncnc2c1c(-c1cccc(O)c1)cn2-c1ccc(OCCn2ccnc2)cc1

Procedure:
1.7 g of 5-(3-benzyloxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine are hydrogenated in a hydrogen atmosphere at normal pressure and about 40° C. for 24 h in 40 ml of methanol in the presence of 0.4 g of 5% palladium/carbon. After filtration through Celite and chromatography on silica gel (methylene chloride/methanol containing 5% of about 5N ammonia in methanol 9:1), 5-(3-hydroxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 221°-223° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[O:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4c(F)cccc4F)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4c(F)cccc4F)cc3)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(2,6-difluorophenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 453 (M++1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Li])CCC.C(=O)=O.CC(C)=O.Cl[Si:37]([CH3:40])([CH3:39])[CH3:38]>O1CCCC1.CCCCCC>[CH3:38][Si:37]([CH3:40])([CH3:39])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([Si:37]([CH3:40])([CH3:39])[CH3:38])=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)C(c1ccc(Br)cc1)(c1ccc(Br)cc1)C(F)(F)F
Reactant: C[Si](C)(C)Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C[Si](C)(C)c1ccc(C(c2ccc([Si](C)(C)C)cc2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
To a solution of 4.62 g (0.1 mole) 2,2-bis(4-bromophenyl)hexafluoropropane in 75 ml of anhydrous tetrahydrofuran was added dropwise 28 ml (0.4 moles) of a 1.4 molar solution of n-butyllithium in hexane while the reaction mixture was cooled in a dry ice-acetone slush. The reaction mixture was stirred for one half hour at -78° C. A dropwise addition of chlorotrimethylsilane (5 ml, 0.04 moles) was then made to the reaction mixture at -78° C. The stirring slurry was allowed to come to ambient temperature over 16 hours. To the reaction mixture was added 100 ml hexane. The organic layer was washed with 2×150 ml saturated sodium chloride solution and 2×150 ml water. The organic layer was dried, filtered, and concentrated to yield the white crystalline product 2,2-bis(4-trimethylsilylphenyl)hexafluoropropane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:6][CH2:7][OH:8].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:32].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:6][C:7]([OH:32])=[O:8]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COC(=O)CC(CCO)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reaction time: 20 h
Yield: 64.4 %

Procedure:
5-Hydroxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]pentanoic acid methyl ester (70 mg, 0.17 mmol) is dissolved in DMF (1.5 mL) at room temperature and pyridinium dichromate (250 mg, 0.66 mmol) is added into it. The mixture is stirred for 20 hr and water (25 mL) is added. The pH of the solution is adjusted to pH 5 by adding acetic acids and the mixture is extracted with EtOAc (3×50 mL). The organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 80% EtOAc in Hexanes with 1% acetic acid affords 48 mg (66%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanedioic acid monomethyl ester. LCMS (ESMS): m/z 439.17 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.N12CCN(CC1)CC2.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22].CCOCC>CN(C=O)C>[CH3:19][N:20]([CH3:24])[C:21](=[S:22])[O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C)cc(O)c1
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc(C)cc(OC(=S)N(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a mixture of 3-methoxy-5-methylphenol (7) (3.39 g, 24.5 mmol) and 1,4-diazabicyclo[2.2.2]octane (5.50 g, 49.0 mmol) in DMF (20 mL) was added dimethylthiocarbamoyl chloride (8) (6.06 g, 49.0 mmol) portionwise. The reaction mixture was stirred at room temperature overnight and 500 mL of ether was added. The organics were washed with water (150 mL), brine (2×50 mL), dried (Na2SO4), and concentrated. Purification by chromatography on silica gel (Hexanes/EtOAc, 4:1) gave O-3-methoxy-5-methylphenyl dimethylcarbamothioate (9) (5.05 g, 91%) as a colourless solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>>[N:30]1([C:14](=[O:15])[C:13]([NH:12][C:10]([C:7]2[CH:6]=[C:5]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:11])([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)[CH3:17])[CH2:33][CH2:32][CH2:31]1
Reactant: C1CNC1
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)N2CCC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (example 147c) and azetidine (CAN 503-29-7) as starting materials and isolated (23 mg, 51%); MS (ESI, m/z): 454.5 (M+H+).