Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][N:14]=[C:13]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[CH:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=1)([CH3:38])[CH3:37]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:36]([O:39][C:40]1[N:41]=[C:42]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[S:15][N:14]=[C:13]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=5)[N:12]=4)[CH:9]=3)[N:4]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:3]=2)[CH:43]=[CH:44][CH:45]=1)([CH3:38])[CH3:37]
Reactant: COc1ccc(CNc2nsc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC(C)C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nsc(-c3ccc4c(c3)c(-c3cccc(OC(C)C)n3)cn4S(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 90 °C
Yield: 43.4 %

Procedure:
A solution of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (0.8 g, 1.29 mmol) and 2-isopropoxy-6-(tributylstannyl)pyridine (0.83 g, 1.95 mmol) in DMF (8 mL) was bubbled with Argon for 15 min. To the above mixture was added CuI (0.124 g, 0.65 mmol) and Pd(PPh3)4 (0.15 g, 0.13 mmol) and argon gas was purged for another 15 min. The reaction was heated at 90° C. for 1 h. The mixture was treated with ice cold water (20 mL) to obtain off white precipitate. The precipitate was filtered, washed with H2O (20 mL) and dried. The solid was purified by basic alumina chromatography (eluent: 20% EtOAc in petroleum ether) to give 5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (0.35 g, 43%) as a white solid. MS (ESI, pos. ion) m/z: 625.2 (M+1); 1H-NMR (400 MHz, CDCl3): δ 9.02 (d, J=1.2 Hz, 1H), 8.10-8.08 (m, 2H), 7.96 (dd, J=8.8, 2.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.64 (t, J=8.0 Hz, 1H), 7.34-7.24 (m, 2H) 4.62 (d, J=5.6 Hz, 2H), 3.80 (s, 3H), 2.35 (s, 3H), 1.46 (d, J=5.6 Hz, 6H).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CC(C)([O-])C.[K+]>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].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.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccnc2)CC1
Temperature: 80 °C
Reaction time: 17 h
Yield: 102.5 %

Procedure:
A toluene solution (6 ml) of 3-bromopyridine (300 mg, 1.89 mmol), piperazine-1-carboxylic acid tert-butyl ester (389 mg, 2.09 mmol), tris(dibenzylideneacetone)dipalladium (43.4 mg, 0.0474 mmol), Xantphos (54.9 mg, 0.0949 mmol) and potassium tert butoxide (469 mg, 4.18 mmol) was degassed under ultrasonic irradiation, and stirred at 80° C. for 17 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water (20 ml) was added, followed by extraction twice with dichloromethane (20 ml). The organic layer was dried over sodium sulfate, followed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1), to obtain a crude product of 4-pyridin-3-yl-piperazine-1-carboxylic acid tert-butyl ester as a yellow liquid (510 mg).
Reaction SMILES: Cl.C(N(C(C)C)CC)(C)C.[C:11]1([CH2:17][O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH:26]=[O:27])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)C(O)=O.[N+:38]([CH3:41])([O-:40])=[O:39]>C(O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.COC(C)(C)C>[N+:38]([CH2:41][C@H:26]([C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:24]=1)[OH:27])([O-:40])=[O:39]
Reactant: O=Cc1cccc(OCCCOCc2ccccc2)c1
Reactant: C[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: COC(C)(C)C
Product: O=[N+]([O-])C[C@@H](O)c1cccc(OCCCOCc2ccccc2)c1
Temperature: -30 °C

Procedure:
Copper (II) acetate and camphoraminomethylpyridine bis-HCl salt (504 mg) were charged to a reactor, followed by ethanol (60 mL) and diisopropylethylamine (1.16 mL). The contents were stirred for 1 h at room temperature, at which time a solution of 3-({3-[(phenylmethyl)oxy]propyl}oxy)benzaldehyde in ethanol (15 g in 15 mL) was charged. The reaction mixture was cooled to −30° C. to −40° C., whereupon nitromethane (33.9 g) was added slowly to the reaction, maintaining a temperature below −30° C., followed by diisopropylethylamine (359 mg). The reaction temperature was maintained at −30° C. for 24-48 h. When the reaction was complete, trifluoroacetic acid (952 mg) was charged to the reaction, and the contents were transferred to a separate reactor containing a room temperature solution of 1 N HCl (75 mL) and t-butyl methyl ether (TBME, 150 mL). After the addition was complete, the layers were allowed to separate and the aqueous phase removed. The organic phase was then washed with water (75 mL) and the aqueous phase removed. The solution of product in TBME was then filtered through a pad of silica gel (15 g) which was rinsed with TBME. The product was stored cold as a solution in TBME, to be swapped to ethanol prior to the subsequent hydrogenation step.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+].C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:28]=1[C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=1)=[O:30].C(N(CC)C(C)C)(C)C>CO.ClCCl.CN(C)C=O.CN(C1C=CN=CC=1)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:12]([NH:26][C:27]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:28]=2[C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=2)=[O:30])=[O:14])[CH2:15][CH2:16]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: Nc1ccc(I)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Agent: C[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 1 h
Yield: 62 %

Procedure:
To a stirring solution of 1-Boc-isonipecotic acid (15.26 g, 66.55 mmol) in methanol (135 mL) was added sodium methoxide (3.8 g, 66.8 mmol). After stirring for 1 h, the solvent was removed in vacuo. A portion of the residue (8.92 g, 35.5 mmol) was suspended in dichloromethane (95 mL) and oxalyl chloride (4 mL, 45 mmol) was added, followed by a couple of drops of N,N-dimethylformamide. After stirring for 1 h, the solvent was removed in vacuo. The residue was suspended in dichloromethane (45 mL) and added to a solution of 2-amino-N-(5-chloropyridin-2-yl)-5-iodobenzamide (8.86 g, 23.7 mmol), N,N-diisopropylethylamine (5 mL, 28 mmol), and 4-(N,N-dimethylamino)pyridine (0.33 g, 2.7 mmol) in dichloromethane (50 mL). After stirring 19 h, the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was slurried in diethyl ether and filtered to give 8.6 g (62%) of a pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=4)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=4)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4cccc(Cl)c4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4cccc(Cl)c4)CC3)nc2c1

Procedure:
To a solution of methyl 3-(4-(3-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (143.5 mg, 0.29 mmol, 1.00 equiv, 91%) in methanol (15 mL) was added a solution of sodium hydroxide (62.8 mg, 1.57 mmol, 5.00 equiv) in water (2 mL) dropwise with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath, then concentrated under vacuum. The resulting solids were washed with methanol yielding 44 mg (34%) of 3-(4-(3-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@:13]3([N:17]([CH3:18])[C:16](=[O:19])[N:15]([C:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=4)[C:14]3=[O:28])[CH2:12][N:11]([CH2:29][C:30]3[S:34][CH:33]=[C:32]([C:35]([OH:37])=[O:36])[CH:31]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:38][Si](C=[N+]=[N-])(C)C.OP(O)(O)=O>C(Cl)Cl.CO.O.CO>[CH3:38][O:36][C:35]([C:32]1[CH:31]=[C:30]([CH2:29][N:11]2[CH2:10][C@@H:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C@:13]3([N:17]([CH3:18])[C:16](=[O:19])[N:15]([C:20]4[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=4)[C:14]3=[O:28])[CH2:12]2)[S:34][CH:33]=1)=[O:37]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1cc(C(=O)O)cs1)C[C@H]2c1ccc(C#N)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)c1csc(CN2C[C@@H](c3ccc(C#N)cc3)[C@]3(C2)C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)N3C)c1
Temperature: 25 °C

Procedure:
To a solution of 5-[(5S*,9R*)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid (example 37) (0.150 g, 0.27 mmol) in DCM/MeOH (5:1 mL) was added trimethylsilyldiazomethane (2.0 M solution in hexane, 0.33 mL, 0.67 mmol) over a period of three minutes at RT. The reaction mixture was stirred at RT for twenty minutes, quenched by the slow addition of acetic acid (approximatly ten drops) and partitioned between DCM (20 mL) and saturated aqueous sodium bicarbonate (15 mL). The DCM layer was washed with brine (20 mL), dried over sodium sulfate and concentrated to yield a thick oil. LC retention time=3.34 min. Column used: YMC S5 combiscreen ODS 4.6×50 mm (4 min. gradient); Solvent A=10% MeOH, 90% H2O and 0.2% H3PO4; solvent B=90% MeOH, 10% H2O, 0.2% H3PO4.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O>[C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC
Solvent: O
Product: CCCCCCCCCCCC(=O)O
Yield: 86 %

Procedure:
As apparent from Table 1, it is found that when the amount of water to be used with respect to 2 mmol of methyl laurate is increased, the yield is increased, and in the water volume between 1 to 8 mL, a highest yield of 86% is obtained at a water volume of 8 mL.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:22])[C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[Cl:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].C([O-])(=O)C.[NH4+]>>[Cl:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:22][C:13]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[C:2]([Cl:1])[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1)=[O:27]
Reactant: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2N)CC1
Reactant: O=C(O)c1cccnc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2NC(=O)c2cccnc2Cl)CC1
Yield: 25 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-(4-methyl-piperazin-1-yl)-8-amino-9H-β-carboline and 2-chloro-nicotinic acid in 25% yield. 1H-NMR (300 MHz, DMSO-d6): δ 2.21 (s, 3H), 2.33 (m, 2H), 2.54(m, 2H), 3.24 (m, 4H), 7.73 (dd, 1H), 8.12 (d, 1H), 8.35 (d, 1H), 8.37 (s, 1H), 8.48 (dd, 1H), 8.61 (dd, 1H), 8.91 (s, 1H), 10.40 (s, 1H), 11.33 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.46 min. MS (M+H+): 455.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[N:3]=1.C([Li])CCC.CN([CH:20]=[O:21])C>CCOCC>[CH3:9][O:8][C:5]1[C:4]([O:10][CH3:11])=[N:3][C:2]([CH:20]=[O:21])=[CH:7][N:6]=1
Reactant: CN(C)C=O
Reactant: COc1ncc(Br)nc1OC
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ncc(C=O)nc1OC
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4.85 gm of 2-bromo-5,6-dimethoxypyrazine in 80 ml of dry ether under N2 at -35° C. was added dropwise 14.5 ml of n butyllithium (1.6N in hexanes). After stirring for 0.5 hours at -35° C. 5.74 ml of dry DMF was added dropwise to the reaction mixture. This dark brown homogeneous solution was stirred at -20° C. for 1 hour and at 25° C. for 0.5 hours, then was quenched with an aqueous solution of NH4Cl. The reaction mixture was extracted with methylene chloride, and the organic fractions were washed with water, brine and dried over MgSO4, and filtered and evaporated to give a red oil. Chromatography on a short silica gel column provided the title aldehyde and its hydrate which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([O:29]CC)=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5]3)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccc(Cn2ccc3cc(NS(=O)(=O)c4ccc(-c5ccccc5)cc4)ccc32)cc1

Procedure:
The title compound was prepared from ethyl N-{4-[(5-amino-1H-indol-1-yl)methyl]benzoyl}phenylalaninate and biphenyl 4-sulfonyl chloride following the procedure of Example 10: MS (ESI) m/z 630; MS (ESI) m/z 628.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]([CH2:16][CH2:17][CH3:18])[C:12](=O)[CH2:13][CH3:14])[CH2:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH2:16]([N:11]([CH2:12][CH2:13][CH3:14])[CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH2:1])[CH:3]=2)[CH2:7]1)[CH2:17][CH3:18]
Reactant: CCCN(C(=O)CC)C1Cc2ccc(N)cc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)C1Cc2ccc(N)cc2C1
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
A solution of N-(5-amino-indan-2-yl)-N-propylpropionamide (2.6 g, 10.5 mmol) in dry diethyl ether (50 mL) was added to a slurry of lithiumaluminum hydride (1.0 g, 26 mmol) in diethyl ether (150 mL) at ambient temperature. After stirring for 1.5 hours water (1.0 mL) followed by 15% sodium hydroxide (1.0 mL) and water (3.0 mL). After stirring for 10 minutes, the inorganic material was filtered off and the resulting solution was evaporated to yield 2.2 g (90%) of the desired product as an oil.:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:10][C:11]=2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[F:25].O1CCCC1.[OH-].[Li+].Cl>O.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[F:25]
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(F)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
In a 50 mL round bottom flask were combined ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (0.245 g, 0.000637 mol), tetrahydrofuran (5.49 mL, 0.0677 mol) and a solution of lithium hydroxide (2.0 M in water, 3.18 mL, 0.00637 mol). The mixture was heated at 80° C. with stirring for 2 days, and then cooled to room temperature and diluted with water. Reaction mixture was then carefully adjusted to pH 5 via addition of 1N HCl and transferred to a separatory funnel containing EtOAc (40 mL). Layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a white solid, which was dissolved in DCM and adsorbed onto silica gel. Column chromatography (4 g column, gradient elution 0-20% MeOH in DCM) then afforded 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylic acid (118) (31 mg, 14%). LC/MS: (FA) ES+ 357, 359; NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 7.48 (t, 0.1=8.1, 1H), 7.24 (dd, J=1.9, 10.5, 1H), 7.08 (dd, J=1.5, 8.3, 1H), 4.24 (s, 2H), 3.71-3.62 (m, 4H), 3.46-3.38 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([OH:16])[CH:9]=2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH3:12])=[C:10]([OH:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccc(Cl)cc2)cc1O
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OCc2ccc(Cl)cc2)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-chloro-benzyloxy)-2-hydroxybenzaldehyde (1.31 g, 5.0 mmol) and sodium cyanoborohydride (1.0 g, 15.9 mmol, Aldrich) in tetrahydrofuran (30 mL) was added methyl orange as an indicator, giving the solution a yellow color; 1N aqueous HCl solution (7.5 mL) was added slowly, keeping the solution orange. The mixture was then stirred overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate three times. The combined organic phase was washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 0-40% ethyl acetate in hexanes to give 5-(4-chloro-benzyloxy)-2-methyl-phenol. (Yield 0.43 g).
Reaction SMILES: [CH2:1](N(C1C(C)=CC2C(C)CCC(C)(C)C=2C=1)C1C=CC(C(OCC)=O)=CC=1)C.C([N:31]([C:43]1[C:52]([CH3:53])=[CH:51][C:50]2[C:49]([CH3:55])([CH3:54])[CH2:48][CH:47]=[C:46]([CH3:56])[C:45]=2[CH:44]=1)[C:32]1[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1)C.C(O)C.[OH-].[K+]>O>[CH2:56]([C:46]1[C:45]2[CH:44]=[C:43]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=3)[C:52]([CH3:53])=[CH:51][C:50]=2[C:49]([CH3:54])([CH3:55])[CH2:48][CH:47]=1)[CH3:1]
Reactant: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)(C)CC=C3C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CC=C3CC)cc1
Temperature: 60 °C
Yield: 92 %

Procedure:
General Procedure E To a solution of ethyl 4-[ethyl(3,5,8,8-tetramethyl-5,6-dihydronaphthalen-2-yl)amino]benzoate, (Compound 19, 0.17 g, 0.45 mmol) and 5 mL of absolute ethyl alcohol was added aqueous 5 M KOH (2 mL). The resulting solution was heated in an 60° C. bath for 24 h. The solution was cooled to room temperature, diluted with water and washed once with 2:1 hexane:ethyl acetate solution, and the layers were separated. The aqueous layer was acidified with HCl 2 N to pH=0-1 and the product extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed to give 0.042 g (92%) of the title compound as an off-white solid.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[C:10]=1[C:16]([O:18][CH3:19])=[O:17].CCOCC>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[C:10]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1=C(OC)CCC1CO
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)C1=C(OC)CCC1C=O
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
25.5 g of chromic oxide were added in small fractions at 15° to 20° C. to a solution of 41 ml of pyridine in 400 ml of anhydrous methylene chloride and the mixture was stirred for 15 minutes and was then cooled to -15° C. A solution of 4.3 g of the product of Step G in 10 ml of methylene chloride was added thereto and after 90 minutes, 50 g of celite and 100 ml of ether were added. The mixture was filtered and the filtrate was washed with ether and evaporated to dryness at 30° C. to obtain methyl (5RS) 2-methoxy-5-formyl-1-cyclopentene-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:20]=[C:19]([CH3:31])[C:18]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:31][C:19]1[CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[C:17]([CH3:16])[C:18]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:15])[CH2:6][O:7][C:8]=3[CH:13]=2)[CH:33]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4C)c3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
A solution of methyl[(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (0.348 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20) to give the title compound (0.442 g, yield 82%) as a colorless oil.