Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Ar].[Li]CCCC.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:24]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: c1ccsc1
Reactant: CCCCCCCCCCCCBr
Agent: [Ar]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cccs1
Temperature: -78 °C
Yield: 95 %

Procedure:
Thiophene (51.2 g, 623 mmol, 1.2 eq) was first placed in a three-necked flask equipped with a dropping funnel and a reflux tube. The atmosphere in the flask was replaced by Ar (argon), 200 ml of dehydrated tetrahydrofran (hereinafter referred to as “THF”) was then added thereto, and the mixture was stirred. The reaction solution was cooled to −78° C., 2.6 M n-BuLi (200 ml, 520 mmol, 1.0 eq) was added dropwise to the cooled solution, and the mixture was stirred for 30 min. The reaction solution was brought to 0° C. and was stirred for 2 hr. Thereafter, the reaction solution was brought to room temperature and was stirred for 15 min, followed by cooling to 0° C. 1-Bromo-n-dodecane (130 g, 520 mmol, 1.0 eq) was added dropwise thereto, and the mixture was stirred at 0° C. for 2 hr. The reaction solution was brought to room temperature, was stirred for 6 hr, and was then refluxed for one hr. The reaction solution was allowed to cool to room temperature and was extracted with diethyl ether, followed by washing with water until pH=7. The extract was dehydrated over Na2SO4, and the solvent was then removed by evaporation. The residue was purified by chromatography on silica gel to give an objective substance 2-dodecylthiophene as a light yellow liquid (about 125 g yield about 95%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.26 (m, 18H), 1.67 (m, 2H), 2.81 (t, 2H, J=7.32 Hz), 6.77 (d, 1H, J=3.42 Hz), 6.90 (dd, 1H, J=3.42 Hz, J=5.37 Hz), 7.09 (d, 1H, J=0.98 Hz, J=4.88 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30]C3CCCCO3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23]C3CCCCO3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1>O1CCCC1.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([OH:30])[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)OC)O[C@H]2C[C@H]1O
Yield: 73.7 %

Procedure:
By proceeding as described in Example 2 but using 435 mg of (13E)-(6RS,9α,11α,15S)-6,9-epoxy-11,15-bis-(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Example 5) dissolved in a mixture of 0.7 ml of tetrahydrofuran and 9 ml of 65% aqueous acetic acid, there were obtained 220 mg of the title compound having the following physical characteristics:
Reaction SMILES: Br[C:2](=[CH2:14])[CH2:3][CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Mg].II.[F:18][C:19]1[CH:26]=[C:25]([F:27])[C:24]([C:28]2[CH:29]=[N:30][CH:31]=[N:32][CH:33]=2)=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1.O>[Si:7]([O:6][CH2:5][CH2:4][CH2:3][C:2](=[CH2:14])[C:21]([C:20]1[CH:23]=[C:24]([C:28]2[CH:33]=[N:32][CH:31]=[N:30][CH:29]=2)[C:25]([F:27])=[CH:26][C:19]=1[F:18])=[O:22])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: C=C(Br)CCCO[Si](C)(C)C(C)(C)C
Reactant: O=Cc1cc(-c2cncnc2)c(F)cc1F
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C=C(CCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(-c2cncnc2)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.99 %

Procedure:
A solution of ((4-bromopent-4-en-1-yl)oxy)(tert-butyl)dimethylsilane (prepared following the procedures of Rostami, Organic Letters, 2007), 9(4), 703-706) (3.30 g, 11.81 mmol) in THF (25 mL) was added to a flask filled with magnesium (0.574 g, 23.62 mmol) and iodine (0.092 g, 0.363 mmol), and the resulting dark brown suspension was stirred at rt for 15 min and then heated under reflux for 45 min. The color changed from brown to deep reddish and the color of iodine faded 10 min under reflux. Eventually, the color of the reaction mixture turned to grey. This regent was cooled to rt and then added to a suspension of 2,4-difluoro-5-(pyrimidin-5-yl)benzaldehyde (Preparation 15, 2 g, 9.08 mmol) in THF (14 mL), and the reaction mixture was stirred at rt for 12 h. Water was added and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated in vacuo to give the crude product. The crude product was purified by silica gel chromatography eluting with 0-35% EtOAc/Hexane to give 5-((tert-butyldimethylsilyl)oxy)-1-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-2-methylenepentan-1-one (0.95 g, 2.270 mmol, 24.99% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ 9.27 (s, 1H), 8.93 (d, J=1.4 Hz, 2H), 7.59 (dd, J=8.2, 7.3 Hz, 1H), 7.20-7.03 (m, 1H), 6.04 (s, 1H), 5.78 (d, J=1.8 Hz, 1H), 3.70 (t, J=6.3 Hz, 2H), 2.62-2.41 (m, 2H), 1.85-1.70 (m, 2H), 0.93 (m, 9H), 0.09 (m, 6H).
Reaction SMILES: [OH:1][C@H:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1.Br[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:27]=[CH:26]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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]>[OH:1][C@H:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]=[C:28]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:27]=[CH:26]3)[C:6](=[O:10])[CH2:5]1
Reactant: Cc1c([C@@H](O)CN2CCNC(=O)C2)ccc2c1COC2=O
Reactant: CS(=O)(=O)c1ccc2cc(Br)ccc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1c([C@@H](O)CN2CCN(c3ccc4nc(S(C)(=O)=O)ccc4c3)C(=O)C2)ccc2c1COC2=O
Temperature: 120 °C

Procedure:
A mixture of 4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (66 mg, 0.23 mmol), 6-Bromo-2-(methylsulfonyl)quinoline [I-14] (65 mg, 0.23 mmol), Pd2(dba)3 (42 mg, 0.045 mmol), Xantphos (53 mg, 0.091 mmol), and Cs2CO3 (110 mg, 0.34 mmol) in DMF (5 mL) was sealed in a microwave tube and purged three times with nitrogen. It was heated to 120° C. for 10 minutes in a microwave reactor. LC showed formation of the product. The material was purified by silica gel flash chromatography, followed by crystallization to give the title product. LC-MS (IE, m/z): 496 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.OP(O)(O)=O>O>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: O=P(O)(O)O
Solvent: O
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A 2 liter flask equipped with a thermometer, stirrer and condenser is charged with 200 g polyphosphoric acid which is heated to 70° C. Thereafter, 40 g of 2,5-di-(p-chloranilino)terephthalic acid is added, the mixture is heated to 145°-150° C. and held at this temperature for 2 hours. 34.9 g water are slowly dropped into the mixture at 130° C. (to 90% H3PO4) and held for two additional hours at 145°-150° C. With the mixture at 140° C., 350 ml water is added over a 30 minute period with the mixture being maintained at 90°-95° C. for an additional 30 minutes. The reaction slurry is filtered, the presscake reslurried in 400 ml water and the pH adjusted to 12.0 by the addition of 50% aqueous sodium hydroxide solution. The pigment suspension is stirred for 30 minutes at 90° C. and filtered. The presscake is washed base free with water and dried yielding 35.62 g of 2,9-dichloroquinacridone pigment manifesting a specific surface area of 28.5 m2 /g.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[N:5](CCCCCCCC)[C:4]=2[CH:3]=1.C1C2NC3C(=CC=CC=3)C=2C=CC=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:3]1[C:4]2[NH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:2]=1
Reactant: CCCCCCCCn1c2cc(Br)ccc2c2ccc(Br)cc21
Agent: CC1(C)OB(c2ccc3c(c2)[nH]c2ccccc23)OC1(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1ccccc12

Procedure:
A solution of 2,7-dibromo-9-octyl-9H-carbazole (220 mg, 0.5 mmol), 9H-carbazole-2-boronic acid pinacol ester (880 mg, 1.5 mmol) and benzyltriethylammonium chloride (50 mg) in a mixture of toluene (20 mL) and aqueous K2CO3 (2M, 8 mL) was degassed by three freeze-pump-thaw cycles. Pd(PPh3)4 (5 mg) was added under argon and degassed by three freeze-pump-thaw again. The mixture was refluxed for 24 h and the organic phase was separated and evaporated. The product was purified by column chromatography (hexane/THF, 4:2) and dried in vacuum. A 220 mg (71%) yield of trimer carbazole was obtained as a light brown powder. 1H NMR (THF-d8, 500 MHz): δ=10.33 (s, 2H), 8.15 (m, 4H), 8.07 (d, J=7.9, 2H), 7.82 (m, 4H), 7.6 (m, 4H), 7.43 (d, J=8.0, 2H), 7.34 (m, 2H), 7.15 (m, 2H), 4.56 (t, J=7.19, 2H), 1.99 (m, 2H), 1.29 (m, 10H), 0.83 (t, J=6.9, 3H). MALDI-TOF MS: m/z 609.33 (100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O1CCCC1>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: OCCOc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cccc(OCCO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 246 %

Procedure:
To a solution of 3-(2-hydroxyethoxy)phenol (864 mg, 5 mmol) in tetrahydrofuran (20 ml) were added potassium carbonate (967 mg, 7 mmol) and t-butyl bromoacetate (0.89 ml, 6 mmol), and the mixture was stirred for 2 hours at room temperature. The reaction was quenched by 10% aqueous citric acid solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 10% aqueous citric acid solution, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution. The organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane:ethyl acetate=3:1) to give the subject compound (3.30 g, 69%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[CH:6][CH:7]=1.[N:29]#[C:30]Br.[OH-].[Na+]>ClCCl.CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[C:30]([NH2:29])=[N:28][C:4]=2[CH:3]=1
Reactant: N#CBr
Reactant: COc1ccc(COc2ccc(CNc3ccc(I)cc3N)cc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(I)ccc43)cc2OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a stirred suspension of 4-iodo-N1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine (8.32 g, 16.97 mmol) in dichloromethane (100 mL) and methanol (50 mL) was added cyanogen bromide solution (5.0 M in acetonitrile, 17.0 mL, 85.00 mmol). The resulting brown reaction mixture was allowed to stir at room temperature. After 16 h, the mixture was treated with 1 N sodium hydroxide solution (250 mL) and was allowed to stir at room temperature. After 15 min, a precipitate formed. The solids were isolated by filtration, washed with water, and dried to afford 4.42 g (51%) of 5-iodo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine as a tan solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8](Cl)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].O>CN1C(=O)CCC1>[C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)Nc1nc(Cl)ncc1C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(N[C@H]2CC[C@H](O)CC2)ncc1C(N)=O
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A mixture of 4-(tert-butylamino)-2-chloropyrimidine-5-carboxamide (0.5 g), trans-4-aminocyclohexanol hydrochloride (0.40 g), Na2CO3 (0.28 g) in NMP (3.5 mL) was heated at 85° C. and held for 6 h. The mixture was cooled to 35° C., and water (10 mL) was added. After 30 minutes, the batch was cooled to 25° C. and held for 1 h. The suspension was filtered, washed with water (2.5 mL) and dried in a vacuum oven at 40° C. with a nitrogen bleed for 24 h to give 4-(tert-butylamino)-2-((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxamide as a white solid (0.6 g, 89%). 1H NMR (DMSO-d6) δ 9.17 (broads, 1H), 8.32 (s, 1H), 7.01 (broads, 1H), 4.52 (d, J=4.5 Hz, 1H), 3.70-3.25 (m, 2H), 1.84 (m, 4H), 1.41 (s, 9H), 1.33-1.16 (m, 4H).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][CH3:11])[NH:7][CH:8]=1.CN(C)C=O.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[N:19]=1>O>[CH3:28][O:27][C:20]1[N:19]=[C:18]([N:7]2[CH:8]=[C:4]([CH3:3])[N:5]=[C:6]2[CH2:9][CH2:10][CH3:11])[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: CCCc1nc(C)c[nH]1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc(C)cn1-c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a suspension prepared of 20.0 g KOH (solid), 25.8 g 4-methyl-2-propyl imidazole and 130 ml dimethyl formamide were added 38.0 g 2-chloro-6-methoxy-3-nitro pyridine in small amounts at a reaction temperature of 5° C. The reaction mixture was stirred for 75 minutes at room temperature. Then the reaction mixture was poured in 600 ml water. The mixture was further stirred for 1 hr. The desired product precipitated during this time. The resulting solid was collected by filtration, washed with 100 ml water for 3 times and dried in a dry box with vacuum (40° C.).
Reaction SMILES: [CH3:1][O:2][N:3]=C1C2C=CN=NC=2OC1.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[O:20][CH2:21][C:22](=O)[C:15]=12>>[CH3:1][O:2][N:3]=[C:22]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][C:14]=2[CH3:13])[O:20][CH2:21]1
Reactant: Cc1ccnc2c1C(=O)CO2
Reactant: CON=C1COc2nnccc21
Product: CON=C1COc2nccc(C)c21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 4-methylfuro[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one;
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11](OCC)=[O:12])[C:4]=2[N:3]=1.O1CCCC1.[AlH4-].[Li+].C(OCC)(=O)C>O>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][OH:12])[C:4]=2[N:3]=1
Reactant: CCOC(=O)c1cccc2[nH]c(C)nc12
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc2c(CO)cccc2[nH]1
Yield: 79.4 %

Procedure:
(a-2) A cooled (0° C.) solution of 10 parts of ethyl 2-methyl-1H-benzimidazole-4-carboxylate in 45 parts of tetrahydrofuran was added dropwise to a suspension of 4 parts of lithium tetrahydroaluminate in 45 parts of tetrahydrofuran. Upon complete addition, the temperature was allowed to reach room temperature. After the addition of ethyl acetate and water, the reaction mixture was filtered over diatomaceous earth. The filtrate was evaporated, yielding 6.3 parts (79.4%) of 2-methyl-1H-benzimidazole-4-methanol as a residue (int. 66).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20](=[O:22])[CH3:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:23]=1.I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH3:33])[CH3:32].CC(C)(C)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:9]1[S:8][C:7]2[CH:23]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[O:11][C:12]1[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20](=[O:22])[CH3:21])=[CH:16][CH:17]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1ccccc1I
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(C)=O)cc3)csc2c1
Agent: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(Oc3ccc(/C=C/C(C)=O)cc3)c(-c3ccccc3C(C)C)sc2c1
Yield: 58.1 %

Procedure:
To a 5 mL microwave vial, added a solution of (E)-4-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2-one (90 mg, 0.277 mmol) in anhydrous DMA (3.0 mL), followed by 1-iodo-2-isopropylbenzene (137 mg, 0.555 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos Palladacycle 1st generation, 22.16 mg, 0.028 mmol), trimethylacetic acid (85 mg, 0.832 mmol) and potassium carbonate (115 mg, 0.832 mmol). The microwave vial was sealed, purged and back-filled with nitrogen. The reaction mixture subjected to microwave irradiation for 2 h at 150° C. Upon completion the reaction was diluted with EtOAc, and washed with water (2×) and brine (1×). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (SiO2, 0-20% EtOAc/heptane) to afford (E)-4-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2-one (71.3 mg, 0.161 mmol, 58% yield). LC/MS (m/z, MH+): 443.0.
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[CH2:8][N:9]([CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([OH:36])=[O:35])[CH:29]=3)[CH:24]=2)[O:19]1)C(OC(C)(C)C)=O)(C)C.Cl>O1CCOCC1>[OH:6][C@H:7]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[CH2:8][NH:9][CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([OH:36])=[O:35])[CH:29]=3)[CH:24]=2)[O:19]1
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(-c3ccnc(C(=O)O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)ccn1

Procedure:
4-{(2R)-2-[([(2R)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}-2-pyridinecarboxylic acid (Example 70, 29 mg, 0.05 mmol) was stirred in an excess of 4M HCl in dioxane at room temperature for 18 hours. The volatile components were removed by rotary evaporation, and the residue was washed with dichloromethane. After drying under vacuum, the title compound was collected as the tri-hydrochloride salt (23 mg, 93%): 1H NMR (300 MHz, CD3OD) δ 9.07 (broad s, 1H), 8.90 (d, 1H), 8.83-8.78 (m, 3H), 8.49 (d, 1H), 8.18 (t, 1H), 7.94-7.89 (m, 2H), 7.20 (d, 1H), 5.52-5.46 (m, 1H), 4.67-4.61 (m, 1H), 3.76-3.57 (m, 2H), 3.51-3.39 (m, 2H), 3.10-3.05 (m, 2H), 2.29-2.20 (m, 1H), 1.95-1.83 (m, 1H); MS m/z 406.2 (MH+ of the free base).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][C:11]1([CH2:17][CH2:18][OH:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][C:11]1([CH2:17][CH:18]=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC1(CCO)CCCCC1)OCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=CCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
A mixture of [1-(2-hydroxy-ethyl)-cyclohexyl]-acetic acid benzyl ester (1.3 g, 47 mmol), dimethyl sulfoxide (0.83 mL, 12 mmol), and N,N-diisopropylethylamine (2.0 mL, 12 mmol) in dichloromethane (20 mL) was cooled to 0° C. and sulfur trioxide-pyridine complex (1.9 g, 12 mmol) was added. The reaction mixture was stirred at 0° C. for 2 h and the reaction was quenched with 0.1 N HCl. The aqueous layer was discarded. The organic extract was washed twice with 0.1 N HCl and brine. The organic extract was dried with sodium sulfate, filtered, and concentrated to dryness to provide the title compound (1.17 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[Na+].[C:25]([Cl:28])(=[O:27])[CH3:26].Cl>CC(C)=O.O>[ClH:28].[C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:27])[CH3:26]
Reactant: CC(C)(C)NCC(O)COc1ccc(O)c2c1CCC(=O)N2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(OCC(O)CNC(C)(C)C)c2c1NC(=O)CC2
Yield: 45.5 %

Procedure:
0.7 g of 8-hydroxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril was suspended in 20 ml of acetone, and 3.0 ml of 1 N sodium hydroxide was added thereto to form a homogeneous solution. 0.2 g of acetyl chloride dissolved in a small amount of acetone was added dropwise to the solution under cooling with water, followed by allowing the mixture to stand under water-cooling for 30 minutes. 2 ml of 1 N hydrochloric acid was added thereto, and the solvent evaporated under reduced pressure. The residue was purified by silica gel column chromatography using chloroformmethanol (8:1 by volume) as an eluent. The solvent was evaporated, and the residue was recrystallized from methanol-diethyl ether to obtain 0.4 g of 8-acetoxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril hydrochloride as colorless flake-like crystals having a melting point of 247°-248° C. (with decomposition).
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH3:37][CH:38]([CH3:78])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[CH:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:63][CH:62]=4)=[CH:55][C:54]=3[C:73]([F:76])([F:75])[F:74])=[CH:49][CH:50]=2)[C:45]1=[O:77])[C:40]([O:42]C)=[O:41]>>[CH3:78][CH:38]([CH3:37])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[CH:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:63][CH:62]=4)=[CH:55][C:54]=3[C:73]([F:75])([F:76])[F:74])=[CH:49][CH:50]=2)[C:45]1=[O:77])[C:40]([OH:42])=[O:41]
Reactant: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)c(C(F)(F)F)c2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)c(C(F)(F)F)c2)cc1
Yield: 79 %

Procedure:
The compound of example 430 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 429.