Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:9](=[O:28])[C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:13]([O:25][CH3:26])=[CH:12][C:11]=1[F:27])C(=O)C)[CH3:2].O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:9]([C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:13]([O:25][CH3:26])=[CH:12][C:11]=1[F:27])=[O:28])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Temperature: 25 °C

Procedure:
To a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-oxobutyric acid ethyl ester prepared in Step VI-1 in ethanol were successively added water (5 ml) and sodium acetate (7.87 g) with stirring at room temperature, and the mixture was stirred for 4 days. Water (20 ml) was added to the reaction suspension at 70° C. and, after confirmation of dissolution, the mixture was cooled to room temperature. A seed crystal (10 mg) of the title compound was added and, after stirring for 1 hr, water (75 ml) was added again, and the mixture was stirred for 4 hr. The precipitated crystals were collected by filtration, washed with 50% ethanol (20 ml) and vacuum dried to give 3-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionic acid ethyl ester (10.3 g, yield 84.5%). This was identified as the title compound by HPLC.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[CH:14]=[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[C:12]([N+:28]([O-:30])=[O:29])=[CH:11][N:10]=1>C1COCC1>[CH:25]([NH:24][C:22]([C@H:19]1[CH2:20][CH2:21][C@@H:16]([NH:15][C:13]2[C:12]([N+:28]([O-:30])=[O:29])=[CH:11][N:10]=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:14]=2)[CH2:17][CH2:18]1)=[O:23])([CH3:27])[CH3:26]
Reactant: COCCO
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c([N+](=O)[O-])cn1
Reaction time: 0.33 h

Procedure:
To an ice-bath cooled solution of 2-methoxyethanol (0.296 mL, 3.76 mmol) in THF (2.3 mL) was added sodium hydride (150 mg, 3.76 mmol), and the mixture was stirred for 20 minutes. To the mixture was added cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (400 mg, 1.174 mmol), and the flask was removed from the ice bath and the reaction was stirred for 2 hours. The reaction was quenched with water and diluted with DCM, washed with water, saturated aqueous NaHCO3, and the organic layer dried over Na2SO4 and filtered through Celite® brand filter aid. The material was purified via flash chromatography using a linear gradient of 0% to 5% of 1% NH4OH in MeOH in CH2Cl2. The title compound was collected as a yellow solid (273 mg, 61% yield).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)c2cc(Br)ccc2-c2ccc(-c3ccccc3-c3ccccc3)cc21
Temperature: 100 °C
Yield: 63 %

Procedure:
A mixture of 35.2 g (100 mmol) of 2,7-dibromo-9,9-dimethyl-9H-fluorene, 21.8 g (110 mmol) of biphenyl-2-ylboronic acid, 2.31 g (2 mmol) of Tetrakis(triphenylphosphine)palladium, 75 ml of 2M Na2CO3, 150 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 12 h. After finishing the reaction. The mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product (26.8 g, 63.0 mmol, 63%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.61 (d, J=7.8 Hz, 1H), 7.55˜7.53 (m, 2H), 7.49˜7.42 (m, 5H), 7.29 (d, J=8.0 Hz, 1H), 7.20˜7.14 (m, 5H), 6.98 (s, 1H), 1.21 (s, 6H)
Reaction SMILES: [S:1]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:2][CH2:3][C:4]([O:6]C)=O.[H-].[Na+].C(=O)(O)[O-].[Na+]>COCCOC>[CH3:13][O:12][C:10]([C:9]1[CH2:8][S:1][CH2:2][CH2:3][C:4]=1[OH:6])=[O:11]
Reactant: COC(=O)CCSCCC(=O)OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1=C(O)CCSC1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
A solution of dimethyl 3,3′-thiodipropionate (30.00 g, 144.0 mmol) in ethylene glycol dimethyl ether (200 mL), under nitrogen, was treated with sodium hydride (7.00 g, 145.8 mmol), and the reaction was heated under reflux for 1.5 h. The reaction mixture was then cooled to 25° C. and was slowly treated with a saturated aqueous sodium bicarbonate solution. The solvent was then removed in vacuo, and the resulting residue was diluted with water (500 mL) and extracted with ethyl acetate 3×300 mL). The combined organic extracts were then washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) followed by a saturated aqueous sodium chloride solution (1×150 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography, performed in two batches, (FLASH 40M, Silica, 9/1 hexanes/diethyl ether) afforded 4-hydroxy-5,6-dihydro-2H-thiopyran-3-carboxylic acid methyl ester (12.89 g, 51.4%) as a colorless oil.
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]\Cl.C(N)CCC.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[C:14]#[CH:15])[CH3:11]>C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:1]/[CH:2]=[CH:3]\[C:15]#[C:14][CH:13]([O:16][CH2:17][CH3:18])[O:12][CH2:10][CH3:11]
Reactant: Cl/C=C\Cl
Reactant: C#CC(OCC)OCC
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: c1ccccc1
Product: CCOC(C#C/C=C\Cl)OCC
Temperature: 25 °C
Reaction time: 4.2 h
Yield: 53 %

Procedure:
Neat cis-1,2-dichloroethylene (4.5 ml, 60 mmol) followed by butylamine (8.0 ml, 81 mmol) was added to a solution of copper iodide (0.90 g, 4.73 mmol) and palladium tetrakis(triphenylphosphine) (1 g, 0.86 mmol) in 40 mL of dry benzene stirring at 25° C. under argon. Immediately thereafter, a solution of 3,3-diethoxypropyne (5 g, 39 mmol) in 10 mL of benzene was added via cannula. The reaction vessel was wrapped in foil to shield it from light, and the reaction mixture was stirred for 4.2 h at 25° C. The dark brown reaction mixture was filtered by suction through a coarse frit and diluted to approximately 10 ml with diethylether. The solution was washed with 75 mL of water and 120 mL saturated brine, and the organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was flash chromatographed on SiO2 using 5%, then 10%, and then 15% diethylether/pentane as eluent to provide the desired product as a clear liquid (3.9 g, 55%).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)=O.[CH3:23][CH:24]([CH3:40])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:29]=1)=[O:26]>>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=2[CH2:1][N:37]2[CH2:38][CH2:39][CH:34]([C:30]3[CH:29]=[C:28]([NH:27][C:25](=[O:26])[CH:24]([CH3:40])[CH3:23])[CH:33]=[CH:32][CH:31]=3)[CH2:35][CH2:36]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: N#Cc1ccc(COc2ccc3ccccc3c2C=O)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c(OCc4ccc(C#N)cc4)ccc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-{[(1-formyl-2-naphthyl)oxy]methyl}benzonitrile and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 518.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:19])[CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])O.[Na+].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[CH:14][C:13]=2[F:19])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
4-(4-amino-2-fluorophenoxy)pyridine-2-carboxylic acid methyl ester (11.5 g) was dissolved in acetone (340 ml) and water (170 ml). To the reaction mixture was added sodium hydrogencarbonate (17.3 g), then benzyl chloroformate (9.79 ml) while stirring in an ice water bath, followed by stirring for 15 min. The reaction mixture was allowed to warm up to room temperature, then stirred for 2 hr. To the reaction mixture cooled in an ice water bath was further added benzyl chloroformate (2.45 ml), followed by stirring for 18 hr. The reaction mixture was concentrated under reduced pressure, and to the resultant residue were added ethyl acetate (500 ml) and brine (200 ml), and liquid-liquid separation was carried out. The separated organic layer was washed with water (100 ml) and brine (200 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the resultant solid was suspended in ethyl acetate (50 ml) and hexane (30 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as a pale yellow solid (9.6 g, 70.6%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([O:24]C)=[O:23])[C:15]=4[N:14]=3)=[C:9]([C:26]([F:29])([F:28])[F:27])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=4[N:14]=3)=[C:9]([C:26]([F:28])([F:27])[F:29])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(CN4CCCC4)cc3C(F)(F)F)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc2[nH]c(-c3ccc(CN4CCCC4)cc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
Methyl 2-(4-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylate (544 mg) and LiOH (95 mg, 4 mmol) were dissolved in THF/H2O (1:1, 24 mL). The reaction was stirred overnight at room temperature, then heated at 50° C. overnight. The solvents were removed in vacuo. The residue was taken up in water and the pH was adjusted to 7-8 with 1N HCl. After allowing the mixture to stirred for 1 hour, the solids were collected by filtration to afford 2-(4-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 159 as a pale solid (170 mg, 2-step yield: 40%). MS (ESI) calcd for C20H18F3N3O2: 389.14; found: 390 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([NH:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22])(=[O:25])[CH3:24]
Reactant: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CCC1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2.7 g of 4-aminoandrosta-4,6-dien-3,17-dione in 10.8 ml of dry pyridine are added 5.4 ml of acetic anhydride at room temperature dropwise. After 90 minutes of additional stirring, the reaction mixture is cooled to 0° C. and worked up by the addition of cold water, followed by extraction with ethyl acetate. The organic phase is separated, washed with saturated NaCl aqueous solution, dried over Na2SO4 and evaporated in vacuo to yield a residue which is purified by column chromatography on silica gel. Elution with ethyl acetate:methanol 9:1 yields 2.6 g of the title compound as yellow crystals, m.p. 235°-236° C. (dec.);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[C:54](=[O:55])[C:53]([C:56](O)=[O:57])=[CH:52][CH:51]=[N:50]2)=[CH:45][CH:44]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CS(C)=O>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:56]([C:53]2[C:54](=[O:55])[N:49]([C:46]3[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=3)[N:50]=[CH:51][CH:52]=2)=[O:57])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=3)[N:9]=[C:10]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:28][CH2:27]3)[C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(N3CCCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(N3CCCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A 100 mL round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1,4-diazepane-1-carboxylate (110.4 mg, 0.1962 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (137.9 mg, 0.5887 mmol, prepared according to Example 19, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (188.1 mg, 0.9811 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (132.6 mg, 0.9811 mmol), N-ethyl-N-isopropylpropan-2-amine (253.6 mg, 1.962 mmol) and DMSO (25 mL). The reaction mixture was stirred at room temperature overnight. The reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (118.3 mg, 77.4%). LRMS (APCI pos): m/e 679 (M−99).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[CH3:35][CH2:36][CH2:37]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[O:19]2)[CH:10]=[C:11]([O:17][CH2:35][CH2:36][CH3:37])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(S(=O)(=O)CCO)c1OCCC
Temperature: 75 °C

Procedure:
A mixture of trans-2-[3-(2-hydroxyethylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (366 mg, 0.74 mmol), n-propyl bromide (0.12 mL, 1.33 mmol) and potassium carbonate (255 mg, 1.85 mmol) in DMF (3 mL) was heated at 75° C. for 1 h. The reaction mixture was cooled and partitioned between ethyl ether and water, and the aqueous layer was re-extracted with ether (2 x). The organic extracts were combined, dried, and evaporated to dryness. The residue was purified by chromatography to give the title compound: Rf 0.43 (hexane-ethyl acetate; 1:2, v/v); NMR (CDCl3) δ 1.05 & 1.09 (2 t, J=7.5 Hz, 2 CH2CH2CH3), 2.85 (t, J=6.5 Hz, OH), 3.65 (m, SO2CH2), 3.95 (m, SO2CH2CH2); 4.03 & 4.15 (2 t. J=6.5 Hz, 2 CH2CH2CH3), 6.63 (s, 2 H, C5ArH), 7.27 & 7.49 (2 d, J=1.5 Hz, C2ArH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:30][C:29](=[O:31])[N:28](CC[Si](C)(C)C)[S:27]1(=[O:39])=[O:38])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][C:20](=[O:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:30][C:29](=[O:31])[NH:28][S:27]1(=[O:39])=[O:38])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][C:20](=[O:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of N-((1R*,2S*)-2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzyl}-cyclohexyl)-acetamide (76 mg, 0.133 mmol) in DMF (3 mL) is added CsF (81 mg, 0.533 mmol) and the mixture is stirred at 90° C. for 1 h. Ethyl acetate is added and the mixture is washed with 1N HCl and brine. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[O:18]([CH2:25][CH2:26][NH2:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:27][CH2:26][CH2:25][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCOc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCOc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-phenoxyethylamine in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH:25]C(=O)OC(C)(C)C)[S:22][N:21]=4)[CH:18]=3)[N:13]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[S:22][N:21]=4)[CH:18]=3)[N:13]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:34])=[O:35])[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C)C)n3)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C)C)n3)c3cc(-c4nsc(N)n4)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a mixture of tert-butyl (3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (0.49 g, 0.8 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. The reaction was stirred for 2 h at RT. The solvent was then removed in vacuo and the residue was triturated with Et2O to give 3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (0.23 g, 56.2%). MS (ESI, pos. ion) m/z: 506.1 (M+1). To a solution of 3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (0.23 g, 0.45 mmol) in 1-4-dioxane (10 mL) was added 10% aq NaOH (5 mL) and the reaction was heated at 100° C. for 2 h. The reaction was quenched with ice cold H2O to give a pale yellow precipitate. The precipitate was filtered, washed with ice cold H2O and dried under vacuum. The crude product was purified with preparative HPLC (eluent: 20-80% AcCN in H2O with 0.1% TFA) to give 3-(3-(6-(isopropylamino)pyrazin-2-yl)-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (45 mg, 28.3%). MS (ESI, pos. ion) m/z: 352.1 (M+1); 1H NMR (DMSO-d6, 400 MHz): δ 11.81 (s, 1H), 9.19 (s, 1H), 8.20-8.18 (m, 2H), 7.92 (dd, J=8.4, 1.2 Hz, 1H) 7.86 (brs, 2H), 7.63 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 4.32-4.29 (m, 1H), 1.29 (d, J=6.4 Hz, 6H).
Reaction SMILES: [NH2:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>ClCCl>[C:24]1([CH:2]([NH:1][C:37](=[O:38])[CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)=[O:12])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(c1ccccc1)C(NC(=O)Nc1ccc(C(F)(F)F)cc1)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NC(c1ccccc1)C(NC(=O)Nc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a solution of [R-(R*,R*)] and [S-(R*,R*)]-N-(2-amino-1,2-diphenylethyl)-N'-[4-(trifluoromethyl)phenyl]urea (0.1 g, 0.25 mmol) in dichloromethane (5 mL) is added phenylacetyl chloride (0.05 g, 0.3 mmol) followed by triethylamine (0.03 g, 0.3 mmol) in one portion. The resulting mixture is stirred 2 hours at room temperature before concentrating in vacuo. The residue is dissolved in diethyl ether and the organic layer washed with aqueous 1N NaOH, aqueous saturated NaCl, and dried over MgSO4. Filtration and concentration gives an oil which is purified by flash chromatography (SiO2, EtOAc/hexane eluent). The resulting solid is recrystallized from ethyl acetate/hexane to give 0.07 g (52%) of desired white solid, mp 233.5°-234° C. NMR (DMSO-d6): 3.46 (dd, 2H, J=26.4, 14 Hz), 5.10 (m, 2H), 6.97-7.19 (m, 20H), 7.57 (s, 4H), 8.82 (d, 1H, J=8.3 Hz), 8.98 (s, 1H). Analysis calculated for C30H26F3N3O2.0.71H2O: C, 67.94; H, 5.21; N, 7.92. Found: C, 67.94; H, 4.84; N, 7.86.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])=O.[NH2:18][NH2:19]>CO>[CH3:14][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=1)[NH:6][C:5]([C:3]1[O:2][CH:1]=[N:18][N:19]=1)=[CH:13]2
Reactant: NN
Reactant: COC(=O)c1cc2cc(C)cc([N+](=O)[O-])c2[nH]1
Solvent: CO
Product: Cc1cc([N+](=O)[O-])c2[nH]c(-c3nnco3)cc2c1
Yield: 20 %

Procedure:
5-Methyl-7-nitro-1H-indole-2-carboxylic acid methyl ester (234 mg, 1 mmol) prepared in Preparation 15 was dissolved in methanol (10 mL), to which was added hydrazine (3 mL). The reaction solution was refluxed for 3 h, and concentrated under reduced pressure. To the concentrate was added trimethylorthoformate (10 mL), and the mixture was refluxed for 8 h. The reaction mixture was distilled under reduced pressure, and the resulting solid was washed with ethyl acetate to give the title compound (49 mg, Yield 20%).