Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50](Br)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:59]1[N:64]=[CH:63][CH:62]=[CH:61][N:60]=1)CCC.O>CN1CCCC1=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50]([C:59]3[N:64]=[CH:63][CH:62]=[CH:61][N:60]=3)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(-c2ncccn2)s1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
A mixed solution of the above 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene 53 (200 mg), tri-n-butyl(2-pyrimidinyl)tin 54 (137 mg) and bis(triphenylphosphine)palladium(II)dichloride (9 mg) in N-methyl-2-pyrrolidinone (5 ml) was stirred at 100° C. four 7 hours under argon atmosphere. The mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and subsequently with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) to give 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(2-pyrimidinyl)-2-thienylmethyl)benzene 55 (93 mg) as pale brown oil. APCI-Mass m/Z 826/828 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10])=[O:5].Cl.[NH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([NH:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:10])=[O:5]
Reactant: NN1CCOCC1
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cl
Product: Cc1ccc(C(=O)NN2CCOCC2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
Compound 424 (50 mg, 0.12 mmol) and N-amino-morpholine hydrochloride (35 mg, 0.25 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 67/33 to 100/0) provided the title compound. 13C NMR (DMSO-d6) δ 194.5, 168.2, 158.9 (dd), 155.8 (dd), 149.5, 139.1, 138.2, 133.7, 133.7, 132.9, 131.3, 129.3, 127.5, 126.5 (dd), 126.5, 124.3 (dd), 114.8, 112.0 (dd), 111.9, 105.1 (dd), 66.0, 19.7
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[C:22]([F:21])([F:31])[F:32])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: FC(F)(F)c1ccccc1CCl
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in place of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide to react with 2-trifluoromethylbenzyl chloride, the title compound was obtained as a white solid (32% yield). m.p. 106-108° C. 1H NMR (500 MHz, CDCl3) δ 7.97-8.04, 7.83, 7.65, 7.55, 7.37, 6.96, 3.77, 3.73, 3.56, 2.63, 1.52, 0.71-0.80, 0.45-0.49, 0.08-0.13. MS (ES+) m/z 434 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](B(O)O)[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCCB(O)O
Product: CCCCCc1ccc(C=O)cc1
Yield: 67.7 %

Procedure:
The compound was synthesized as in Example 3.1 using 4-bromobenzaldehyde (250 mg, 1.35 mmol) in place of 5-bromo-2-formylfuran and pentylboronic acid (259 mg, 2.23 mmol) in place of hexylboronic acid to give 4-pentylbenzaldehyde (161 mg, 68%). Used without further characterization.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36].O>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (14.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.70 g). To the solution was added 60% sodium hydride (142 mg) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the mixture was added 1-bromo-3-methyl-2-butene (0.83 ml), and the mixture was stirred at 60° C. for 60 hours. After cooled to room temperature, the mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl/acetate=4/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methyl-2-butenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.71 g).
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8]([OH:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]([O:5][CH3:6])=[O:4].CO[C:18](OC)([CH3:20])[CH3:19].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO>C(Cl)Cl>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][CH:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:15][C:18]([CH3:20])([CH3:19])[O:1]1)=[O:4]
Reactant: COC(C)(C)OC
Reactant: CCOC(=O)CC(O)CC(O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CC1CC(C(=O)OC)OC(C)(C)O1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 1-methyl 6-ethyl 2,4-dihydroxyadipate (1.5 g, 6.81 mmol) in methylene chloride (60 ml), dimethoxypropane (1.672 ml, 78 mmol) and pyridinium p-toluenesulfonate (251 mg, 1 mmol) were added and stirred under reflux conditions for one hour, followed by further stirring at 50° C. for one hour while azeotropically removing methanol with methylene chloride. Then, after adding methylene chloride (60 ml), the mixture was again stirred at 50° C. for one hour to remove methylene chloride (50 ml). To the residue, water was added, and the mixture was extracted with methylene chloride. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=5:1) to give pure 2-methoxycarbonyl-4-ethoxycarbonylmethyl-6,6-dimethyl-1,5-dioxane (1.29 g, 4.99 mmol). Yield, 73 %.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(N(CC)CC)C.Cl[C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>O1CCCC1>[C:25]1([C:23]([O:1][C:2]2[CH:7]=[C:6]([Si:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[CH:4][C:3]=2[C:12](=[O:14])[CH3:13])=[O:24])[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1
Reactant: CC(=O)c1ccc([Si](C)(C)C)cc1O
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)Oc2cc([Si](C)(C)C)ccc2C(C)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Under ice-cooling, to a solution of 832 mg (4 mmol) of 2'-hydroxy-4'-trimethylsilylacetophenone in 20 ml of tetrahydrofuran were added dropwise successively, 0.61 ml (4.4 mmol) of triethylamine and 874 mg (4.4 mmol) of methyl p-chloroformylbenzoate with stirring. The mixture was stirred at room temperature for 1 day and filtered. The filtrate was evaporated and the residue was dissolved in AcOEt. The organic solution was washed with H2O, aqueous sodium bicarbonate solution and brine, dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel [eluent: n-hexane-AcOEt (5:1)] to give 1.40 g of pale yellow viscous liquid (yield 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]([S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12])=[CH2:10]>C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH2:15][CH2:14][S:11](=[O:13])(=[O:12])[CH2:9][CH2:10]2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: C=CS(=O)(=O)C=C
Solvent: CCO
Product: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Reaction time: 1 h

Procedure:
A suspension of 8.74 g of 4-aminophenol in 190 ml of ethanol is added dropwise at 50° to 11.34 g of divinyl sulfone, whereupon rinsing is carried out with 50 ml of ethanol and then the mixture is heated to boiling under reflux under argon for 3 hours. After cooling, the mixture is treated with 480 ml of water and stirred for 1 hour at 0°. The precipitated crystals are removed by filtration under suction, washed with 20 percent ethanol and water and dried. By recrystallization from dichloromethane/methanol/ether there is obtained 4-(p-hydroxyphenyl)-tetrahydro-4H-1,4-thiazine 1,1-dioxide of melting point 153°-155°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C(O)C.C(=O)(O)[O-].[Na+]>O>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[OH:15])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cnc2cc(Cl)ccc2c1O
Temperature: 25 °C
Yield: 46.2 %

Procedure:
7-Chloro-3-nitro-4-hydroxyquinoline (4.48 g, 20 mmol), tin (II) chloride dihydrate (22.6 g, 100 mmol) and ethanol (200 mL) were combined and then heated at reflux for 4 hours. The reaction mixture was cooled to ambient temperature and then poured into water (250 mL). The mixture was brought to neutral pH by the addition of saturated sodium bicarbonate and then filtered to remove tin salts. The filtrate was extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 1.8 g of 3-amino-7-chloro-4-hydroxyquinoline as a green powder.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[S:9])=[CH:3][CH:2]=1.CI.[CH2:19](O)C>O>[CH3:19][S:9][C:8](=[N:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCO
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Solvent: O
Solvent: CI
Product: CSC(=Nc1ccccc1)Nc1ccccc1
Temperature: 25 °C

Procedure:
To a 2 l flask were added 342 g of thiocarbanilide, 240 g of methyl iodide and 350 cc of ethanol and the mixture was refluxed for 2 hours. After cooling the mixture to a room temperature, a small amount of water was added and the mixture was allowed to stand to precipitate the raw product, which was then filtered off and dissolved in 12 l of hot water. After filtration, the filtrate was converted to an alkaline solution by addition of NaOH to precipitate the product. The product was filtered and washed well until the filtrate became neutral. After drying, the product was recrystalized in 1 l of ethanol to give S-methyl-N,N'-diphenylisothiourea.
Reaction SMILES: [C:1]1([C:7]([NH:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:42]>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]([N:15]=[C:16]([Cl:42])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(NC(=Cc1ccccc1)c1ccccc1)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)C(Cl)=NC(=Cc1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
18.4 g of the product of Step A were refluxed for 4 hours in 320 ml of methylene chloride, 18.22 g of triphenylphosphine and 6.7 ml of carbon tetrachloride. 9.11 g of triphenylphosphine in 3.35 ml of carbon tetrachloride were added without reflux and after heating for a further one hour at reflux, the mixture stood for 16 hours at ambient temperature. The solvents were expelled under reduced pressure and the residue was triturated in a 1-1 mixture of ether and methylene chloride, then separated. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica and eluted with methylene chloride to obtain 18.7 g of the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][N:18]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:17]1=[O:36])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:17]1=[O:36])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2cccs2)CN(CC(=O)O)C1=O

Procedure:
Following the procedure described in Example 43, 0.3 g of isomer B of t-butyl α-[6-(1-ethoxycarbonyl-3-phenylpropylamino)-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [obtained as described in Example 49(h)], was de-t-butyrated using trifluoroacetic acid to afford the desired product as a crystalline powder in a yield of 83 mg. The product softened at about 135° C. and melted at 168° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[C:17]([C:22]([O:24][CH3:25])=[O:23])=[N:18][CH:19]=[CH:20][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: COC(=O)c1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1nccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
To a 350 mL sealable tubed was added 4-(pyridin-2-ylamino)phenol (5.16 g, 27.7 mmol), methyl 3-chloropyrazine-2-carboxylate (4.78 g, 27.7 mmol), and cesium carbonate (9.93 g, 30.5 mmol) with DMSO. The tube was sealed and heated to 100° C. for three days. After cooling to temperature, the reaction was diluted with water and extracted with ethyl acetate. The combined, dark brown organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The brown residue was adsorbed onto silica under high vacuum and flash purified on (0.5 to 10% MeOH/DCM), affording the product as a pale tan solid (7.44 g, 23.1 mmol, 83%). MS (ESI, pos. ion) m/z: 323.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(CC)CC)C.[CH3:20][Si:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([S:24]([CH2:23][CH2:22][Si:21]([CH3:29])([CH3:28])[CH3:20])(=[O:26])=[O:25])[N:9]=2)[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Reactant: Cc1cc(C=O)cc2cn[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C=O)cc2cn(S(=O)(=O)CC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
To a suspension of 7-methylindazole 5-aldehyde (3.0 g, 18.7 mmol) in methylene chloride (150 mL) was added triethylamine (7.83 mL, 56.2 mL, 3 equiv) followed by dropwise addition of neat 2-trimethylsilanyl-ethanesulfonyl chloride (5.60 g, 28.1 mmol, 1.5 equiv). The mixture gradually became homogeneous and was allowed to stir at room temperature for 16 h. The solution was concentrated to a minimum amount of methylene chloride and then subjected to flash column chromatography on silica gel (1:4 ethyl acetate/hexanes) to give 4.7 g (77%) of the product as a pale yellow solid. 1H-NMR (CDCl3, 300 MHz) δ 9.98 (s, 1H), 8.77 (s, 1H), 8.09 (s, 1H), 7.64 (s, 1H), 3.64-3.58 (m, 2H), 2.65 (s, 3H), 0.88-0.82 (m, 2H), 0.01 (s, 9H).
Reaction SMILES: [C:1]([N:4]([CH2:28][C@@H:29]1[O:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]3[CH2:46][CH2:45][S:44](=[O:48])(=[O:47])[CH2:43][CH2:42]3)=[C:37]([F:49])[CH:36]=2)[CH2:30]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:27])[C@@H:11]([NH:19]C(OC(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.[ClH:58]>C1COCC1>[ClH:58].[C:1]([N:4]([CH2:28][C@@H:29]1[O:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]3[CH2:42][CH2:43][S:44](=[O:47])(=[O:48])[CH2:45][CH2:46]3)=[C:37]([F:49])[CH:36]=2)[CH2:30]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:27])[C@@H:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: COc1ccccc1
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
2(S)-tert-Butoxycarbonylamino-3-phenyl-propionic acid (acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamoyloxy)-methyl ester (12 g) (0.78 g, 1.1 mmol), anisole (0.5 mL) and THF (20 mL) are cooled to 0° C. Hydrogen chloride (4 M in dioxane, 8 mL, 33.1 mmol) is added in a dropwise manner. After complete addition, the ice-bath is removed and the mixture is stirred at RT overnight. Under reduced pressure, the mixture is concentrated to one-half of its original volume. Ether is then added dropwise to the mixture while stirring, resulting in the formation of a solid. The solid is collected via filtration, rinsed with ether and ethyl acetate, and dried under vacuum to give the title compound in 63% yield (0.45 g). 1H NMR (400 MHz, CD3OD): δ 7.50 (dd, 1H), 7.39-7.24 (m, 7H), 6.02 (d, 1H), 5.97 (d, 1H), 4.86 (m, 1H), 4.50 (dd, 1H), 4.18 (m, 2H), 4.09 (dd, 1H), 3.83 (dd, 1H), 3.35 (m, 3H), 3.21 (m, 2H), 3.11 (m, 2H), 2.53 (s, 3H), 2.34 (m, 2H), 2.16 (m, 2H). MS-APCI (m/z+): 341, 385, 606.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([OH:17])[CH:12]=1.C(Cl)Cl>COCCOC.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>[C:1]1([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([OH:17])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: Oc1cc(-c2ccccc2)ccn1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (164 mg, 0.14 mmol) was added to a stirred suspension of phenylboronic acid (345 mg, 2.84 mmol) and 4-bromo-2-hydroxypyridine (494 mg, 2.84 mmol) in DME (10 mL). The reaction mixture was stirred under an argon atmosphere for 90 min. Degassed 2N potassium carbonate solution (aq) (10 mL) was added and the reaction mixture stirred with heating at 90° C. for 72 h. The solvent was evaporated in vacuo, and the residue partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate (×2). The organics were combined, dried over Na2SO4 and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with DCM with a gradient to 5:95 methanol:DCM afforded 4-phenylpyridin-2-ol (311 mg, 1.82 mmol, 64%) M.S. (ESI) (m/z): 172 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[NH2:15][C:9]1[C:8]([O:7][C:6]2[CH:16]=[C:2]([I:1])[C:3]([O:20][CH3:21])=[CH:4][C:5]=2[CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=[C:11]([NH:14][C:31](=[O:32])[CH2:30][Cl:29])[N:10]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)CCl)nc2N)cc1I
Temperature: 25 °C
Yield: 61.8 %

Procedure:
5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (3.6 g, 9 mmol) and 5.1 mL triethylamine was added to 120 mL dry THF, and the reaction mixture was cooled in an ice bath and stirred under nitrogen atmosphere. Chloroacetyl chloride (1.8 mL, 22.5 mmol) dissolved in 5 mL THF was added dropwise, and the reaction mixture was stirred for four hours, during which time the reaction mixture was allowed to slowly warm to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting oil was purified by flash chromatography 0%-20% “Magic Base”/methylene chloride) to give 2.65 g of N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-2-chloro-acetamide as the major fraction.
Reaction SMILES: N[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].N([O-])=O.[Na+].[ClH:17]>C(O)(=O)C.P(=O)(O)(O)O.O>[Cl:17][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1cnn(C)c1N
Reactant: Cl
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnn(C)c1Cl
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 44.3 %

Procedure:
23.7 g of ethyl 5-amino-1-methylpyrazole-4-carboxylate is dissolved in a mixture of 50 ml of concentrated hydrochloric acid, 34 ml of acetic acid and 28 ml of phosphoric acid. A solution of 10 g of sodium nitrite in 25 ml of water is added dropwise to the solution while cooling at -4° C. to -6° C. and stirring over a period of 35 minutes to prepare the diazonium salt solution. While cooling at 3° C. to 4° C., the diazonium salt solution is added dropwise to 140 ml of concentrated hydrochloric acid containing 13.9 g of cuprous chloride over a period of 45 minutes. The mixture is stirred at the same temperature for 1 hour, poured into 2l of ice water, and extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution, a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution in that order, and dried over anhydrous sodium sulfate. Ethyl acetate is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent, ethyl acetate:toluene=1:1) to give 11.7 g of the titled compound. Yield 44.3%.