Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18])([CH3:4])([CH3:3])[CH3:2].C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:15]=[C:16]([CH2:17][OH:18])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C=O)cc1-c1ccncc1C(C)(C)O[SiH2]C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CO)cc1-c1ccncc1C(C)(C)O[SiH2]C(C)(C)C
Reaction time: 1 h

Procedure:
3-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-4-yl]-4-methoxy-benzaldehyde (160 mg) was dissolved into ethanol (3 mL) and treated with sodium borohydride (85 mg). The reaction mixture was stirred for 1 hour, diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield {3-[3-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-4-yl]-4-methoxy-phenyl}-methanol as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([O:28]C)=[O:27])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([C:26]([OH:28])=[O:27])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cc1nc2ccc(C(=O)O)cc2c(-c2ccccc2)c1CNC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of methyl 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-phenylquinoline-6-carboxylate (0.58 g, 1.3 mmol) in tetrahydrofuran (6 ml)-methanol (6 ml) was added 1N aqueous sodium hydroxide solution (3 ml), and the mixture was stirred at 50° C. for 2 hrs. The reaction mixture was partitioned between tetrahydrofuran (50 ml)-ethyl acetate (50 ml) and 0.1N hydrochloric acid (100 ml) and the aqueous layer was extracted twice with tetrahydrofuran (25 ml)-ethyl acetate (25 ml). The organic layers were combined, washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from diisopropyl ether-ethyl acetate to give 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-phenylquinoline-6-carboxylic acid (0.56 g, 99%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH:23]=2)=[CH:20][C:19]([C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])=[CH:36][N:35]=2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:53])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>CCOC(C)=O>[Br:53][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:23]=[C:22]([C:21]3[C:16]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:17][CH:18]=[C:19]([C:34]4[CH:39]=[CH:38][C:37]([S:40]([CH:43]([CH3:45])[CH3:44])(=[O:41])=[O:42])=[CH:36][N:35]=4)[CH:20]=3)[O:26][N:25]=2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CBr)cc4)no3)c2)nc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
tert-Butyl N-tert-butoxycarbonyl-N-[5-(5-isopropylsulfonyl-2-pyridyl)-3-[3-(p-tolyl)isoxazol-5-yl]-2-pyridyl]carbamate (245 mg, 0.3860 mmol) was suspended in EtOAc (2.5 mL) followed by the addition of NBS (89.31 mg, 0.5018 mmol) and AIBN (6.338 mg, 0.03860 mmol). The mixture was heated to 85° C. and placed under a bright lamp for 2 hours. The reaction mixture was cooled to ambient temperature and washed with saturated aqueous NaHCO3/brine (1:1, ×2), dried (MgSO4), filtered and concentrated in vacuo to give the impure sub-title compound as a pale brown foam. This was used in the next step without any further purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Ni]>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(CN2CCCCC2)cc1

Procedure:
37.0 g of 4-(piperidin-1-yl-methyl)-nitrobenzene are dissolved in 300 ml of methanol, 8.0 g of Raney nickel are added and the mixture is hydrogenated for 85 minutes with 3 bars of hydrogen at room temperature. The catalyst is filtered off and the filtrate is evaporated down.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:22]2[NH:27][C:26](=[O:28])[C:25]([Cl:29])=[CH:24][CH:23]=2)=[CH:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17]2)=[CH:10][CH:9]=1.O.[Cl-].[NH4+]>C(#N)C>[Cl:29][C:25]1[C:26](=[O:28])[NH:27][C:22](/[C:14](/[C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=2)=[CH:15]/[C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17]2)=[CH:23][CH:24]=1
Reactant: O=C1CC[C@H](C=C(c2ccc(CBr)cc2)c2ccc(Cl)c(=O)[nH]2)N1
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1CC[C@H](/C=C(\c2ccc(CN3CCCC3)cc2)c2ccc(Cl)c(=O)[nH]2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Separately, pyrrolidine (0.424 mL) was added to a solution of 6-{1-[4-(bromomethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-one (E:Z=1:2 mixture) (206 mg) in acetonitrile (8.24 mL) at room temperature, and the mixture was stirred at room temperature for one hour. Water and a saturated ammonium chloride solution were sequentially added to the reaction solutions at room temperature, and the mixtures were combined, followed by extraction with chloroform. The organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by preparative TLC (chloroform:methanol=5:1) to give the title compound as a white solid (70 mg, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][CH2:14][CH2:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:27][CH:28]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)COc1ccc(CCN)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)NCCc2ccc(OCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 10.35 g. (50 mMol) 4-methoxybenzenesulphonyl chloride and 50 ml. pyridine is added dropwise at 0°-10° C. in the course of 5 minutes to a solution of 11.2 g. (50 mMol) ethyl 4-(2-aminoethyl)-phenoxyacetate in 125 ml. anhydrous pyridine. The reaction mixture is allowed to warm up to ambient temperature and then kept at 60° C. for 45 minutes. Subsequently, the reaction mixture is evaporated to half its volume in a vacuum, then poured into ice-water and acidified with hydrochloric acid. The precipitated viscous mass is dissolved in toluene and the toluene phase successively extracted with dilute hydrochloric acid, an aqueous solution of sodium bicarbonate and water. After drying over anhydrous calcium chloride, the solution is evaporated in a vacuum and the residue triturated with some diethyl ether, crystallization thereby takes place. The product is filtered off with suction and recrystallized from a very small amount of diethyl ether. There are thus obtained 13.0 g. (66% of theory) ethyl 4-[2-(4-methoxybenzenesulphonylamino)-ethyl]-phenoxyacetate; m.p. 82°-83° C.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH2:12][NH2:13].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[ClH:1].[ClH:1].[NH:3]1[C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH2:12][NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1
Reactant: NCc1cc2ccncc2[nH]1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1cc2ccncc2[nH]1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.1 %

Procedure:
A mixture of (1H-pyrrolo[2,3-c]pyridin-2-yl)methylamine dihydrochloride (Example 84) (110 mg, 0.50 mmol), nicotinic acid (62 mg, 0.50 mmol), diisopropylethylamine (0.44 mL, 2.5 mmol), EDCI (110 mg, 0.55 mmol) and HOBt (cat.) in methylene chloride (2.9 mL) and DMF (3 mL) was stirred at room temperature under a nitrogen atmosphere overnight (18 h). The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with water. The water layer was concentrated to dryness. The residue was dissolved in ethanol (10 mL) and 2 N HCl in Et2O (10 mL) was added. Methanol (ca. 5 mL) was added to dissolve the majority of material. The remaining brown precipitate was filtered off and discarded. The filtrate was concentrated, and the resulting solid was triturated with EtOH (ca. 4 mL), filtered, and dried to provide N-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)nicotinamide dihydrochloride (31 mg, 19%) as a tan solid: 1H NMR (500 MHz, CD3OD) δ4.99 (2H, s), 7.00 (1H, s), 8.03 (1H, d, J=6.0 Hz), 8.17-8.24 (3H, m), 8.77 (1H, s), 9.04-9.12 (3H, m), 9.38 (1H, s); ESI MS m/z 253 [C14H12N4O+H]+; HPLC (Method A) >99% (AUC), tR=7.78 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[C:23]2[C:18](=[C:19]([OH:24])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.CCCCCC.O>[C:26]1([CH2:25][CH2:13][C:14]2[C:23]3[C:18](=[C:19]([OH:24])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccnc2c(O)cccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Oc1cccc2c(CCc3ccccc3)ccnc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
A solution of 0.60 ml (4.2 mmol, 2.2 eq.) of diisopropylamine in 10 ml of dry tetrahydrofuran was cooled to -78° C. and 1.6 ml (3.8 mmol, 2 eq.) of 2.4M n-butyl lithium in hexane was added dropwise. The reaction was warmed to 0° C., stirred for 15 minutes and 0.30 g (1.9 mmol) of 4-methyl-8-quinolinol (see Example 1A) in 10 ml of dry tetrahydrofuran was added. The temperature was maintained at 0° C. for 24 hours, then was cooled to -78° C. and 0.23 ml (1.9 mmol, 1 eq.) of benzyl bromide was added. The reaction was stirred at -78° C. for one hour then stirred at room temperature for one hour. Water was added and this was extracted with ether. The organic layers were washed with saturated ammonium chloride, brine, dried (magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography (silica gel, 1:4 ethyl acetate:petroleum ether) and recrystallization (petroleum ether) gave 240 mg of the title compound as pale green crystals: melting point 102°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:34])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:34][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][C:2]=2[Cl:1])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)COc1ccc(-c2cccnc2)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(-c3cccnc3)cc2Cl)cc1Cl

Procedure:
The product was prepared according to general working method I from (2-chloro-4-pyridin-3-yl-phenoxy)-acetic acid (136b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH:25]([NH:28][CH3:29])([CH3:27])[CH3:26]>>[CH:25]([N:28]([CH3:29])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:27])[CH3:26]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CNC(C)C
Product: CC(C)N(C)CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
The product from Example 1C and isopropyl(methyl)amine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 319 (+H)+;
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: ClCc1ccccn1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(Cc3ccccn3)C2=O)CC1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride (2.4 equivalents) and 2-(chloromethyl)pyridine hydrochloride, to give the desired product as a light yellow foam (67%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:23][N:22]([CH3:24])[CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.[OH-].[Pd+2].[OH-]>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH:20]4[CH2:23][N:22]([CH3:24])[CH2:21]4)[CH2:18][CH2:19]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:28]=1
Reactant: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cc4F)ncn3)CC2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 49.5 %

Procedure:
After adding 20% palladium hydroxide (150 mg) to a solution of 4-(1-methylazetidin-3-yl)piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (69.1 mg) in tetrahydrofuran, the mixture was stirred for 7 hours at room temperature under a hydrogen atmosphere. The catalyst was then filtered. The filtrate was concentrated to provide the title compound (31.8 mg, 64.2%) as a yellow oil.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([NH:17][C@H:18]2[C@@H:22]3[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@@H:21]3[C@@H:20]([O:28][CH2:29][CH2:30][OH:31])[CH2:19]2)=[N:8][C:9]([S:13][CH2:14][CH2:15][CH3:16])=[N:10][C:11]=1[Cl:12].C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:12][C:11]1[C:6]2[N:5]=[N:1][N:17]([C@H:18]3[C@@H:22]4[O:23][C:24]([CH3:26])([CH3:27])[O:25][C@@H:21]4[C@@H:20]([O:28][CH2:29][CH2:30][OH:31])[CH2:19]3)[C:7]=2[N:8]=[C:9]([S:13][CH2:14][CH2:15][CH3:16])[N:10]=1
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A solution of sodium nitrite (148 mg, 2.14 mmol, 1.12 equiv.) in water (1 mL) was added to a solution of 2-((3aR,4S,6R,6aS)-6-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (800 mg, 1.91 mmol, 1.00 equiv.) and acetic acid (680 mg, 11.33 mmol, 5.90 equiv.) in toluene (9 mL). The resulting solution was stirred at about 20° C. for about 30 minutes, and then the pH value of the solution was adjusted to 8-9 by adding potassium carbonate. Following standard extractive workup with ethyl acetate (3×10 mL), the resulting residue was purified by silica gel column (ethyl acetate/petroleum ether (1:10)) to give the title product as a yellow oil (370 mg; yield=45%). 1H NMR (300 MHz, CDCl3) δ: 5.54-5.56 (q, J1=2.4 Hz, J2=6.3 Hz, 1H), 5.21-5.25 (m, 1H), 4.90 (d, J=6.3 Hz, 1H), 4.05-4.09 (m, 1H), 3.50-3.66 (m, 4H), 3.23 (t, J=7.5 Hz, 2H), 2.68-2.72 (m, 1H), 2.58 (m, 1H), 1.81-1.89 (m, 2H), 1.57 (s, 3H), 1.39 (s, 3H), 1.12, (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[C:12]([CH3:23])[C:11]([C:24]([O:26]CC)=[O:25])=[N:10]1.[OH-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=2)=[C:12]([CH3:23])[C:11]([C:24]([OH:26])=[O:25])=[N:10]1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(N(C)C)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(N(C)C)cc1
Yield: 39.1 %

Procedure:
Ethyl 1-(2,4-dichlorophenyl)-5-[4-(dimethylamino)phenyl]-4-methyl-1H-pyrazole-3-carboxylate (1 eq, 39 mg, 0.072 mmol) and lithium hydroxide (3 eq, 5.2 mg, 0.215 mmol) was heated at 65° C. in tetrahydrofuran (3 mL) and water (3 mL) for 16 h. The reaction was quenched with a small amount of 10% HCl. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-10% methanol/dichloromethane with 1% acetic acid to yield 1-(2,4-dichlorophenyl)-5-[4-(dimethylamino)phenyl]-4-methyl-1H-pyrazole-3-carboxylic acid (11 mg, 39%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.36 (s, 3H) 2.84-3.05 (m, 6H) 6.60 (d, J=7.35 Hz, 2H) 6.97 (d, J=7.44 Hz, 2H) 7.20-7.37 (m, 2H) 7.42 (br. s., 1H)
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@:8]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C:20]1[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[CH2:18][CH:19]=1)[CH2:10][CH2:9]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH2:1]=[C:24]1[CH2:23][CH2:22][C@H:21]2[C:20]3[C@H:11]([CH2:10][CH2:9][C@:8]12[CH3:7])[C:12]1[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=1[CH2:18][CH:19]=3
Reactant: C[C@]12CC[C@H]3C(=CCc4cc(O)ccc43)[C@@H]1CCC2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C1CC[C@H]2C3=CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (1.9967 g, 5.5892 mmol) and potassium t-butoxide (627.2 mg, 5.589 mmol) suspended in 6.1 ml of anh. DMSO under argon were 1 h in an oil bath (71-83° C., after which equilin (300.0 mg, 1.118 mmol) in 6.1 ml of anh. DMSO was added via syringe. See FIG. 161. After stirring a further 70 min., the reaction mixture was poured into 40 ml of ice water and extracted three times with 25 ml portions of ether. The combined organic extracts were washed with 25 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography (15% ethyl acetate/hexanes on silica gel) followed by preparative TLC (20% ethyl acetate/hexanes on silica gel GF, 1000μ thickness) gave an opaque white film (162.3 mg, 0.6093 mmol, 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])=[CH:16][C:10]=3[C:9]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.[CH3:30][C:31]([NH2:34])([CH3:33])[CH3:32]>>[C:31]([NH:34][C:20]([C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][C:11]3[S:12][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[C:9]([C:26]([NH:27][CH3:28])=[O:29])[C:10]=3[CH:16]=2)[CH:25]=[CH:24][CH:23]=1)=[O:21])([CH3:33])([CH3:32])[CH3:30]
Reactant: CC(C)(C)N
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)O)c3)cc12
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)NC(C)(C)C)c3)cc12

Procedure:
5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzo[b]thiophene-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.15 mmol) and 2-methylpropan-2-amine (0.016 g, 0.22 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.42 (s, 1H), 8.16 (s, 1H), 8.07 (s, 1H), 7.96 (s, 2H), 7.82 (s, 3 H), 7.66 (s, 2H), 7.57 (s, 1H), 7.37 (s, 2H), 2.78 (s, 3H), 1.42 (s, 9H). LCMS: retention time: 3.218 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 461 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.II.Br[C:17]1[C:22](Br)=[C:21](Br)[C:20](Br)=[C:19](Br)[C:18]=1Br>C1COCC1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:17]1[CH:22]=[C:21]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:20]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:19][C:18]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: Brc1c(Br)c(Br)c(Br)c(Br)c1Br
Agent: II
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2-c2cc(-c3ccccc3-c3ccccc3)c(-c3ccccc3-c3ccccc3)cc2-c2ccccc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dry Mg turnings (3.9 g, 0.16 mol) and 30 mL of anhydrous THF were added to a 1 L 3-necked round-bottomed flask equipped with a condenser, a nitrogen inlet, an additional funnel and a magnetic stirring bar. 4-Bromobiphenyl (37.2 g, 0.16 mol) was dissolved in 150 mL of THF and placed in an additional funnel. The reaction flask was placed in a 50° C. oil bath and one crystal of iodine was added. Once the reaction started 4-bromobiphenyl was added dropwise to the reaction. After addition, the brownish reaction was heated at reflux for another hour and then cooled to room temperature. A suspension of hexabromobenzene (11.0 g, 0.02 mol) in 150 mL of THF was added dropwise from an additional funnel to the reaction and the mixture was stirred at room temperature overnight. The reaction was quenched with ice and 8% hydrochloric acid and extracted with 400 mL of methylene chloride. The organic layer was washed with saturated sodium chloride solution and dried over magnesium sulfate. Solvent was evaporated and the crude product was washed with hexane and filtered to give pure product.