Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.CC(O)=O.[C:12]1([S:18]([N:21]2[C:31]3[C:32]4[C:23]([CH2:24][NH:25][CH2:26][C:27]=4[CH:28]=[CH:29][CH:30]=3)=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C1COCC1.CC#N>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:25]1[CH2:24][C:23]2=[CH:22][N:21]([S:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)(=[O:19])=[O:20])[C:31]3[C:32]2=[C:27]([CH:28]=[CH:29][CH:30]=3)[CH2:26]1
Reactant: O=Cc1ncc[nH]1
Reactant: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CNC2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CN(Cc1ncc[nH]1)C2

Procedure:
The experimental for Example 2 was followed using 1H-imidazole-2-carbaldehyde (16 mg, 0.18 mmol), AcOH (46 μL, 0.81 mmol), Na(OAc)3BH3 (51 mg, 0.24 mmol) and 1-(phenylsulfonyl)-1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline, Example 1 (27 mg, 0.08 mmol) in dry THF (4 mL). Preparative HPLC (YMC column 150×30 mm, 32-62% MeCN, 0.1% TFA). This gave 1.7 mg of the title compound, as a brown gum. MS m/z 379 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:9][C:8]([CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[C:27]([F:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:34][C:27]1[C:28]([OH:33])=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH3:18])[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:2]=1[F:1]
Reactant: Cc1cc(C(=O)O)c(F)c(-c2cccc(F)c2)c1
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Reaction time: 1 h
Yield: 23.1 %

Procedure:
To a stirred solution of 2-fluoro-3-(3-fluorophenyl)-5-methyl-benzoic acid (400 mg, 1.65 mmol, 1.1 eq) in CH2Cl2 (10 mL) was added oxalylchloride (0.5 mL, 5.9 mmol, 4.0 eq) and DMF (2 drops). The reaction was stirred for 1 h, then the solvent removed in vacuo and the residue dissolved in THF (10 mL). The solution was then added dropwise to a mixture of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (212 mg. 1.50 mmol, 1.0 eq) and NaHCO3 (492 mg, 5.90 mmol, 4.0 eq) in THF (10 mL) at room temperature. The reaction was stirred overnight then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:3) to give the title compound as a solid (130 mg, 24%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1C=CC=CC=1.C(OCC)C>[N:1]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: C1CCNCC1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Piperidine(1.87 ml, 18.9 mmol) was added dropwise to a solution of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene(9 ml), stirred for 2 hours at a room temperature, diluted with ethyl ether, washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 1.26 g of the titled compound. (Yield 81.8%)
Reaction SMILES: [CH3:1][C:2]1([C:22]#[C:23][CH2:24][CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:7][CH2:6][C:5]2[C:8]([CH3:21])=[C:9]([O:14]CCCCCC)[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1>[Ni].C(O)C.C(OCC)(=O)C>[CH3:13][C:10]1[C:11]([CH3:12])=[C:4]2[C:5]([CH2:6][CH2:7][C@:2]([CH2:22][CH2:23][CH2:24][C@@H:25]([CH2:26][CH2:27][CH2:28][C@@H:29]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH3:36])[CH3:37])([CH3:1])[O:3]2)=[C:8]([CH3:21])[C:9]=1[OH:14]
Reactant: CCCCCCOc1c(C)c(C)c2c(c1C)CCC(C)(C#CCC(C)CCCC(C)CCCC(C)C)O2
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 6 h
Yield: 101.2 %

Procedure:
A mixture of [2S-(4R*,8R*,)]-3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-1-tridecynyl)-6-(pentylmethoxy)-2H-1-benzopyran, (200 mg, 0.39 mmol) and 40 mg of Raney Nickel in 5 mL of ethanol and 5 mL of ethyl acetate was hydrogenated at 25° C. and atmospheric pressure for 6 h. Workup in the usual manner and purification of the crude product by chromatography on silica gel (eluent 1:5 ether-hexanes) gave 170 mg of (2R,4'R,8'R)-α-tocopherol as a pale yellow oil, identical in all aspects with a known sample.
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([CH:9]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[S:3][CH2:2]1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[Br:24][C:6]1[CH:7]=[C:8]2[C:12]3=[C:4]([S:3][CH2:2][CH2:1][N:11]3[CH:10]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH:9]23)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C(C1)c1cccc3c1N2CCS3
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2C(C1)c1cc(Br)cc3c1N2CCS3
Temperature: -10 °C
Reaction time: 0.67 h

Procedure:
The tert-butyl 1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (2.00 g, 6.02 mmol) was dissolved in anhydrous DMF (50 mL) and then cooled in an ice/acetone bath at −10° C. for 20 min. Next, N-bromosuccinimide (1.18 g, 6.62 mmol) was added in one portion. The reaction mixture was stirred for 40 min at −10° C., then poured over an ice/water mixture (300 mL). The resulting suspension was stirred at room temperature for 30 min, and extracted with diethyl ether (4×100 mL). The organic extracts were pooled together, washed with brine and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, tert-butyl 5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate was obtained as a yellow foam (2.24 g, 91%). 1H NMR (300 MHz, CDCl3) δ1.47 (s, 9H), 1.77 (m, 2H), 3.46-3.48 (m, 4H), 2.87-3.48 (m, 6H), 6.93 (s, 1H), 6.97 (s, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[C:23]([NH2:28])[C:24]([NH2:27])=[CH:25][CH:26]=2)[CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:28][C:23]1[CH:22]=[C:21]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)[CH:26]=[CH:25][C:24]=1[NH:27][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][N:9]=1)=[O:13]
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(NC(=O)c3n[nH]c4ncc(Br)cc34)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid Compound 1c (2.095 g, 8.66 mmol), 4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine Compound 14a (1.79 g, 8.68 mmol), HATU (3.29 g, 8.66 mmol) and DIPEA (4 mL, 28.7 mmol) in DMF (70 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (10% to 90% of ethyl acetate in hexanes) to yield 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid [2-amino-4-(4-methyl-piperazin-1-yl)-phenyl]-amide Compound 14b (2 g, 54% yield) as a brown powder. 1H NMR (300 MHz, CD3OD) δ 8.81 (d, 1H, J=2.1 Hz), 8.66 (d, 1H, J=2.1 Hz), 7.42 (d, 1H, J=8.7 Hz), 7.11 (dd, 1H, J=2.7, 8.7 Hz), 7.03 (d, 1H, J=2.7 Hz), 3.92 (b, 2H), 3.65 (b, 2H), 3.31 (b, 2H), 3.16 (b, 2H), 2.81 (s, 3H); MS (ESI) m/z: 431 (M+H+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH3:30][C:31]([NH2:37])([CH2:34][CH2:35][CH3:36])[CH2:32][NH2:33].[Cl:38][C:39]1[CH:40]=[C:41]([O:52][CH2:53][C:54]2[C:59]([F:60])=[CH:58][CH:57]=[CH:56][C:55]=2[F:61])[C:42]2[N:43]([C:45]([C:49](O)=[O:50])=[C:46]([CH3:48])[N:47]=2)[CH:44]=1>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[NH2:37][C:31]([CH3:30])([CH2:34][CH2:35][CH3:36])[CH2:32][NH:33][C:49]([C:45]1[N:43]2[CH:44]=[C:39]([Cl:38])[CH:40]=[C:41]([O:52][CH2:53][C:54]3[C:55]([F:61])=[CH:56][CH:57]=[CH:58][C:59]=3[F:60])[C:42]2=[N:47][C:46]=1[CH3:48])=[O:50]
Reactant: CCCC(C)(N)CN
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCC(C)(N)CNC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Cl)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
191 mg (0.62 mmol) of TBTU and 0.25 ml (2.27 mmol) of 4-methylmorpholine and 72 mg (0.62 mmol) of rac-2-methylpentane-1,2-diamine were added to 200 mg (0.57 mmol) of 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 16A in DMF (2.0 ml), and the reaction mixture was stirred at RT overnight. 36 mg (0.31 mmol) of rac-2-methylpentane-1,2-diamine and 0.06 ml (0.57 mmol) of 4-methylmorpholine were then added, and stirring was continued at RT overnight. The mixture was diluted with water/TFA and purified by preparative RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). The product fraction was concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off and concentrated. The residue was purified by silica gel chromatography (dichloromethane/methanol: 10:1, then dichloromethane/2N ammonia in methanol 20:1). This gave 189 mg (73% of theory, purity 99%) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:35][CH2:34][CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCN3CCOCC3)c2n1

Procedure:
Prepared by the method as described in Example 4, using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and 2-morpholinoethanamine (1.5 equiv.). The title compound was obtained as a white solid (65% yield). MS (apci) m/z=469.1 (M+H).
Reaction SMILES: C[Mg+].[Br-].[CH2:4](OCC)C.CON(C)[C:12]([C:14]1[N:15]=[C:16]([CH3:23])[O:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:13]>>[CH3:23][C:16]1[O:17][C:18]([C:19]([F:20])([F:21])[F:22])=[C:14]([C:12](=[O:13])[CH3:4])[N:15]=1
Reactant: CCOCC
Reactant: CON(C)C(=O)c1nc(C)oc1C(F)(F)F
Agent: C[Mg+]
Agent: [Br-]
Product: CC(=O)c1nc(C)oc1C(F)(F)F
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of MeMgBr in diethyl ether (3 M, 0.63 ml, 1.89 mmole) was added at 0° C. a solution of 2-methyl-5-trifluoromethyl-oxazole-4-carboxylic acid methoxy-methyl-amide (300 mg, 1.26 mmole) and stirring was continued at 22° C. for 1 h. The mixture was washed with 1 M aqueous HCl and H2O, the organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/AcOEt (4:1) to give the title compound (155 mg) as a colorless oil. MS: m/z=193 [M]+.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[C:14]2=[N:15][NH:16][CH:17]=[C:13]2[C@@H:12]([CH:18]2[CH2:20][CH2:19]2)[N:11]1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.Cl>O1CCOCC1>[CH:18]1([C@@H:12]2[C:13]3[C:14](=[N:15][NH:16][CH:17]=3)[CH:10]([CH2:9][OH:8])[NH:11]2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1C(CO[Si](C)(C)C(C)(C)C)c2n[nH]cc2[C@H]1C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: OCC1N[C@H](C2CC2)c2c[nH]nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4R)-tert-butyl 6-((tert-butyldimethylsilyloxy)methyl)-4-cyclopropyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (35) (1.38 g, 3.51 mmol) was covered with HCl in dioxane (4 N, 5 mL).). The reaction mixture was stirred at rt for 1 hr after which it was concentrated under vacuum to give ((4R)-4-cyclopropyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-yl)methanol (36). Retention time (min)=0.203, method [1], MS (m/z) 180.2 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.O.[Cl:9][C:10]1[S:14][C:13]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20](=[O:41])[N:21]([CH:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)[C:22]3=[O:27])=[O:16])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Cl:9][C:10]1[S:14][C:13]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20](=[O:41])[N:21]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:22]3=[O:27])=[O:16])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc2c1C(=O)N(C1CCNCC1)C2=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
50 ml of a mixture of TFA and water (9:1) are added dropwise to an ice-cooled mixture of 1.82 g (3.71 mmol) of tert-butyl 4-(4-{[(5-chloro-2-thienyl)carbonyl]-amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)tetrahydro-1(2H)-pyridine-carboxylate in 50 ml of chloroform. The ice-cooling is removed and the mixture is stirred at room temperature for 1.5 h and then concentrated. The residue is taken up in dichloromethane/methanol and washed with sat. sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The crude product can be purified further by crystallization with ether. Yield: 1.185 g (78% of theory); MS (DCI, NH4): m/z (%)=390 (M+H, 100).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>C(#N)CC.O>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH2:44]2)=[CH:41][CH:42]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCCC12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCCCC12
Temperature: 90 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.43 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (103 mg, 0.41 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (94.0 mg, 0.41 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The solids were collected to afford the title compound (69.9 mg, 39%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.47 (s, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.21 (d, J=9.1 Hz, 2H), 6.97 (d, J=1.8 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.50 (d, J=12.9 Hz, 1H), 3.83 (dd, J=11.2, 2.7 Hz, 1H), 3.34 (d, J=5.6 Hz, 2H), 3.01-3.17 (m, 4H), 2.55-2.65 (m, 1H), 2.37-2.48 (m, 4H), 1.98-2.08 (m, 1H), 1.85 (d, J=12.4 Hz, 1H), 1.63 (d, J=12.6 Hz, 1H), 1.32-1.56 (m, 3H). [M+H] calc'd for C, 22; H, 26; ClN, 5; O, , 412; found, 412.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][CH2:10][C:11]2[S:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]=2[CH3:16])=[CH:4][C:3]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].[Cl-].[NH4+]>CC(C)=O>[CH3:22][C:3]1[CH:4]=[C:5]([C:8](=[O:21])[CH2:9][CH2:10][C:11]2[S:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]=2[CH3:16])[CH:6]=[CH:7][C:2]=1[O:1][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(=O)CCc2sc3ccccc3c2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C(=O)CCc2sc3ccccc3c2C)cc1C
Temperature: 0 °C
Yield: 87.3 %

Procedure:
To an ice-cold suspension of the above-mentioned 1-(4-hydroxy-3-methylphenyl)-3-(3-methylbenzothiophen-2-yl)propan-1-one (200 mg, 0.644 mmol) and potassium carbonate (178 mg, 1.29 mmol) in acetone (6.4 mL) was added slowly ethyl bromoacetate (0.14 mL, 1.3 mmol). The mixture was heated under reflux for 3 hours, to which was added saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), to give the titled compound as a colorless oil (223 mg, yield 87%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[CH:11][C:6]2=[CH:5][CH:4]=1)#[CH:2].[C:12](O)(=[O:14])C.C1N2CN3CN(C2)CN1C3.C(=O)([O-])O.[Na+]>O>[C:1]([C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[C:11]([CH:12]=[O:14])[C:6]2=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc2cc[nH]c2n1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C#Cc1ccc2c(C=O)c[nH]c2n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
6-Ethynyl-1H-pyrrolo[2,3-b]pyridine (0.016 g, 0.11 mmol) was successively added with acetic acid (0.1 mL), water (0.2 mL), and hexamethylenetetramine (0.023 g, 0.17 mmol), and then the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was cooled to room temperature, and then added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 6-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.016 g, 85%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.BrC1C=C(O)C=CC=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]2[C:23]=1[C:24](=[O:41])[C:25](=[O:40])[N:26]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39].FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:41][C:24]1([C:9]2[C:8]([OH:11])=[CH:7][C:3]3[O:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)[C:23]2[C:27](=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:22]=2[O:21][CH3:20])[N:26]([CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[C:25]1=[O:40]
Reactant: COCCOCCN1C(=O)C(=O)c2c(OC)ccc(OC)c21
Reactant: Oc1ccc2c(c1)OCCO2
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: COCCOCCN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2c(OC)ccc(OC)c21

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3-bromophenol, and 4,7-dimethoxy-1[-2-(2-methoxyethoxy)ethyl]-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-one was obtained (53%): MS (ES+) m/z 443.9 (M−17).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:35][C@H:36]([OH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[C:20]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:35][C@H:36]([OH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[C:20]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:19]=2)=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(CCCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
To a solution of methyl 4′-[3-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-3-(cyclohexyloxy)-4-biphenylcarboxylate (147 mg) in methanol (2.94 ml) was added 1N sodium hydroxide (0.5 ml) and the mixture was stirred at room temperature for 18 hours, at which time the starting material was still remained. The mixture was warmed to 50° C. and stirred for 3 hours, at which time the reaction was complete. After cooling to room temperature, the mixture was quenched by the addition of 1N hydrochloric acid (0.5 ml) and diluted with ethyl acetate (10 ml). The mixture was with water (10 ml×2) and brine (10 ml), and dried over magnesium sulfate. Filtration followed by evaporation gave 4′[3-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-3-(cyclohexyloxy)-4-biphenylcarboxylic acid (141 mg) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]([C:21]4[N:22]([CH3:27])[N:23]=[C:24]([CH3:26])[CH:25]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]([C:21]4[N:22]([CH3:27])[N:23]=[C:24]([CH3:26])[CH:25]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1cc(C(=O)Nc2cccc(Cc3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cccc(Cc3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Temperature: 78 °C
Yield: 66.9 %

Procedure:
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (0.100 g, 0.278 mmol) and ethyl formate (0.068 mL, 0.834 mmol) were dissolved in anhydrous ethanol (0.55 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.519 mL, 1.39 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a brown precipitate. The suspension was filtered yielding an light brown solid as the pure 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (0.072 g, 0.186 mmol, 67%).