Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.[NH2:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:30]=[C:31]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:32]([Cl:35])=[N:33][CH:34]=2)[CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2S(C1C=CC=CC=1)(=O)=O>C(Cl)Cl>[Cl:35][C:32]1[N:33]=[CH:34][C:29]([C:27]2[CH:26]=[C:25]3[C:21]([CH:22]=[N:23][NH:24]3)=[C:20]([NH:19][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)=[O:10])[CH:28]=2)=[CH:30][C:31]=1[NH:36][S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Nc1cc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Reactant: Cc1cccc(C(=O)O)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc3[nH]ncc23)n1
Reaction time: 0.25 h
Yield: 41.8 %

Procedure:
6-Methyl-2-pyridinecarboxylic acid (43 mg) was dissolved in DCM (2 ml) and 1-chloro-N,N,2-trimethyl-1-propen-1-amine (0.042 ml) was added. The reaction was stirred for 15 mins. N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-chloro-3-pyridinyl}methane sulfonamide (100 mg) in DCM (4 ml) was added and the reaction left at RT. The reaction was evaporated to dryness. IPA (3 ml) was added to the residue followed by 2M NaOH (aq) (3 ml) and the reaction was left overnight. The solution was neutralised using 2M HCl (aq) and then concentrated. The precipitate that formed was filtered then DMSO was added to the precipitate. Attempts to filter the solid failed so the reaction was blown down under a stream of nitrogen. The residue was redissolved in DMSO (0.5 ml) and purified by MDAP (method E). The pure fraction was evaporated to dryness to give title compound (40 mg).
Reaction SMILES: BrC[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][CH:4]=1>CN(C=O)C>[CH3:14][O:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(CBr)c2ccccc12
Solvent: CN(C)C=O
Product: COc1cccc2ccccc12

Procedure:
In analogy with Example 44, the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(4-methoxy-1-naphthyl)-methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in abs. DMF using TB AF. [The starting compound for preparing the naphthylmethyl substituent, 1-bromomethyl-4-methoxynaphthalene, is obtained from 1-methoxynaphthalene (Fluka, Buchs, Switzerland) by brominating with I2 /Br2 in CHCl3, reacting the resulting bromide by means of a Grignard reaction and working up with CO2 to form the corresponding acid; reaction of the latter with lithium aluminium hydride to form 1-hydroxymethyl-4-methoxynaphthalene (reduction); and reaction of the latter with PBr3, thereby yielding the desired starting material (see Can. J. Chem. 59, 2629 (1981))].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([NH:11][CH:12]=[C:13]([C:19]([O:21]CC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7](=[O:24])[C:6]=2[CH:25]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]3[C:19](=[O:21])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:11][C:8]=3[C:7](=[O:24])[C:6]=2[CH:25]=1
Reactant: CCOC(=O)C(=CNc1coc2ccc(Cl)cc2c1=O)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(=O)c3cc(Cl)ccc3oc2c1=O
Yield: 92.5 %

Procedure:
Diethyl {[(6-chloro-4-oxo-4H-1-benzopyran-3-yl)amino]methylene}propanedioate (5.0 g, 0.0137 mole) was added to diphenyl ether (30 ml) at 200°. The reaction mixture was refluxed (bath temp. 280°-290° ) for 60 min. The product, which crystallized out on cooling, was filtered off and washed with ether. Recrystallization from DMF gave white crystals (4.05 g, 93%), m.p. 330°-338° (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:24](/[CH:23]=[CH:22]/[C:17]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=2)(=[O:26])=[O:25])=[C:3]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Product: N#Cc1ccc(NS(=O)(=O)/C=C/c2ccc(Cl)c(Cl)c2)c(S(N)(=O)=O)c1

Procedure:
The title compound was synthesized as described for Example 194 a), starting from 2-amino-5-cyanobenzenesulfonamide and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride (1.5 equiv.). Purification by column chromatography, using chloroform/methanol (95:5-9:1) as the eluent.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[BH4-].[Na+].O>O1CCCC1>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:14][OH:15])=[CH:16][CH:17]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1ccc(CO)cc1
Reaction time: 1 h

Procedure:
4-(Phenylsulfonyl)benzaldehyde (prepared according to the method of Ulman et al., J. Org. Chem. (1989), 54 (19), 4691–2; 12.3 g, 50 mmol) was dissolved in tetrahydrofuran and methanol was added, followed by careful addition of sodium borohydride (2.0 g, 52.9 mmol). The reaction was stirred for 1 hour before pouring into water and extracting with ethyl acetate. The organic layer was dried over MgSO4 and evaporated in vacuo to give [4-(phenylsulfonyl)phenyl]methanol. This was treated with phosphorus tribromide and heated to reflux for 16 hours. The cooled reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with dichloromethane, to give 1-(bromomethyl)-4-(phenylsulfonyl)benzene (10.1 g, 65%). δH (500 MHz, CDCl3): 7.96–7.90 (4H, m), 7.59–7.56 (1H, m), 7.52–7.49 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1
Reactant: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: COc1ccc2c(c1/C=C\CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.2 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperazine-1-carboxylate (0.0761 g, 0.196 mmol) obtained in Example B46, Step 4 in ethanol (5 mL) was added with Lindlar's catalyst (0.0700 g), and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and then the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl]piperazine-1-carboxylate (0.0603 g, 79%).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:13]([CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)[CH3:14])(=[O:24])=[O:23]
Reactant: CNCCC#Cc1cccc(CF)n1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: CN(CCC#Cc1cccc(CF)n1)S(=O)(=O)c1ccccc1Cl
Yield: 31 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (70 mg, 0.36 mmol) and 2-chlorobenzene-1-sulfonyl chloride (92 mg, 0.44 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, Cyclohexane/AcOEt:70/30 as eluent) to afford 41 mg of 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzenesulfonamide as a yellow oil (Yield: 31%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](O)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])(O)(=O)=O.[K+].C(N1C(C(C2C=CC=CC=2)=CCC2C=CC=CC=2)=CN=C1)C1C=CC=CC=1>C(OCC)C>[CH2:1]([N:8]1[C:12]([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCc1ccccc1)(c1ccccc1)c1cncn1Cc1ccccc1
Agent: C(Cc1ccccc1)=C(c1ccccc1)c1cncn1Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Product: c1ccc(CCC(c2ccccc2)c2cncn2Cc2ccccc2)cc1

Procedure:
1-benzyl-5-(1-hydroxy-1,3-diphenylpropyl)-1H-imidazole is treated with anhydrous potassium hydrogen sulphate at 150° C. as described in Example 7 e). The double bond of the obtained intermediate, 1-benzyl-5-(1,3-diphenyl-1-propenyl)-1H-imidazole, is hydrogenated as described in Example 7 f). M.p. of the hydrochloride salt is 154°-174° C. (from diethylether).
Reaction SMILES: C([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18]C)=[O:17])=[CH:7][CH:6]=1)(=O)C.[OH-]>CO>[NH2:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(NC(C)=O)c2c1OCCCC2
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(C(=O)O)c2c1CCCCO2

Procedure:
To a solution of 5 g (19.0 mmol) of methyl 6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboylate in 10 ml of methanol is added 10 ml of a 10% aqueous solution hydroxide solution in a single portion at room temperature. The reaction mixture is heated to reflux and maintained at that temperature for 2 hours. After cooling, methanol is removed in vacuo and the residue is diluted with water. The pH of the solution is adjusted to 7 with 1N HCl and the solution is extracted with CH2Cl2. The combined organic extracts are dried over MgSO4, filtered and concentrated. Flash chromatography (30% EtOAc/hexanes) gives 6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:47][C:48]([F:59])([F:58])[C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:52]3[CH:53]=[CH:54][C:49]([C:48]([F:59])([F:58])[F:47])=[CH:50][CH:51]=3)=[CH:2][CH:38]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 87 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoylamino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethyl phenyl boronic acid (0.133 mg, 0.69 mmol) by following general procedure D yielding the title compound (98 mg, 85%) as a white solid.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([OH:17])[CH:8]=2)=[O:3].[H-].[Na+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>CN(C)C=O.O>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([O:17][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH:8]=2)=[O:3]
Reactant: NC(=O)Nc1[nH]c2cc(O)ccc2c1C(N)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Nc1[nH]c2cc(Oc3ccc([N+](=O)[O-])cc3)ccc2c1C(N)=O
Reaction time: 0.08 h
Yield: 61.4 %

Procedure:
Under ice-cooling, 2-aminocarbonylamino-6-hydroxyindole-3-carboxamide (Compound No.2-1, 1.3 g, 5.5 mmol) in anhydrous N,N-dimethylformamide (7 mL) was added dropwise to a suspension of 60% sodium hydride (450 mg, 11 mmol) in anhydrous N,N-dimethylformamide (15 mL) over a period of 5 minutes and the mixture was stirred for 5 minutes. Moreover 4-fluoronitrobenzene (640 μL, 6.0 mmol) was added thereto, and the mixture was stirred for 15 minutes at room temperature and stirred overnight at 60° C. After cooling, the reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (200 mL) and brine (200 mL), and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained solid was filtered off and washed with a mixed solvent of chloroform-diethyl ether solution (1:2, 60 mL). The solid was dried at 40° C. for 1 hour under reduced pressure to give the title compound (1.2 g) as a brown solid (59%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[CH:15]=[CH:16][S:17][C:10]=2[C:9]=1[OH:18])=[O:7])[CH2:2][CH2:3][CH3:4].[C:19]([Si](C)(C)C)#[CH:20].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:19]#[CH:20])[C:11]2[CH:15]=[CH:16][S:17][C:10]=2[C:9]=1[OH:18])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCOC(=O)c1nc(Br)c2ccsc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: C#Cc1nc(C(=O)OCCCC)c(O)c2sccc12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 21.8 %

Procedure:
A mixture of 4-bromo-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester (example 44a, 165 mg, 0.5 mmol), ethynyl-trimethyl-silane (87 μl, 0.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.015 mmol), CuI (5 mg, 0.025 mmol), and triethylamine (1.5 ml) was heated in a microwave oven at 100° C. with stirring for 15 min. After cooling to ambient temperature water (20 ml) was added and the mixture was extracted with diethylether (1×30 ml). The organic phase was dried over MgSO4. Then silica gel was added and the mixture concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with ethyl acetate:hexanes=9:1 and in vacuo concentration gave the title compound as a dark oil (30 mg); MS-(+)-ion: MS-(+)-ion: M+1=275.9.
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([CH:21]2[O:23][CH2:22]2)=[CH:19][CH:18]=1.[H-].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([CH2:22][CH:21]([C:20]3[CH:24]=[CH:25][C:17]([CH3:16])=[CH:18][CH:19]=3)[OH:23])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: Cc1ccc(C2CO2)cc1
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCc2c(c3ccccc3n2CC(O)c2ccc(C)cc2)C1
Yield: 17.9 %

Procedure:
2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400 mg, 2.0 mmol), 4-methylstyrene oxide (2.01 g, 15 mmol) and NaH (240 mg, 6 mmol) were heated in DMF (6 mL) at 120° C. for 16 h to obtain 120 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL). 1H NMR (CDCl3, TFA salt) δ (ppm): 13.40-13.10 (bs, 1H), 7.40-7.30 (t, 2H), 7.29-7.10 (m, 6H), 5.07-4.95 (m, 1H), 4.75-4.60 (t, 1H), 4.25-4.02 (m, 3H), 3.75-3.65 (m, 1H), 3.40-3.0 (m, 5H), 2.35 (S, 3H), 1.47-1.40 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5](I)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[Cl:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([C:4]1[C:5]([C:25]2[CH:24]=[CH:23][C:22]([Cl:21])=[C:27]([Cl:28])[CH:26]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(I)c(C(N)=O)c2C1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2nc(-c3ccc(Cl)c(Cl)c3)c(C(N)=O)c2C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 84.6 %

Procedure:
To a stirred solution of Intermediate 156C (9 g, 23 mmol), (3,4-dichlorophenyl) boronic acid (6.57 g, 34.4 mmol) in 1,4-dioxane (150 mL) and water (10 mL) was added K3PO4 (14.61 g, 68.8 mmol) and the reaction mixture was purged with nitrogen for 15 min. PdCl2(dppf)-CH2Cl2 (1.124 g, 1.377 mmol) was added and the reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (3×80 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude reaction mixture was purified by silica gel chromatography (40 g REDISEP® column, eluting with 65% EtOAc in hexanes). Fractions were collected and concentrated to afford Intermediate 199A as pale yellow solid (8 g, 85%). MS(ES): m/z=411.0 [M+H]+; 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.92-7.87 (m, 1H), 7.69-7.64 (m, 2H), 7.44-7.18 (m, 2H), 4.74 (s, 2H), 4.17 (t, 2H), 3.84 (t, 2H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][CH:2]([CH:8]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH2:9][CH:10]=[CH2:11])[CH2:3][C:4]([O:6]C)=[O:5]>[OH-].[K+].CO>[OH:1][CH:2]([CH:8]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH2:9][CH:10]=[CH2:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: C=CCC(C(C)CC)C(O)CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(C(C)CC)C(O)CC(=O)O
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
Methyl 3-hydroxy-4-sec-butylhept-6-enoate (14.40 g, 67.2 mmol) was dissolved in a 2 N potassium hydroxide-methanol solution (200 mL), and the solution was stirred at room temperature for 13.5 hours. The solvent was distilled off under reduced pressure. To the residue, water and diethyl ether were then added, and the aqueous layer was neutralized with 2 N hydrochloric acid. Diethyl ether was added thereto, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a yellow oil substance (12.70 g, 94%).
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[C@@H:29]2[C@:24]([OH:30])([CH2:25][CH2:26][CH2:27][O:28]2)[C@H:23]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C@@H:23]2[CH2:22][CH2:21][C@@H:20]([CH2:19][OH:18])[C@@H:29]3[C@@:24]2([OH:30])[CH2:25][CH2:26][CH2:27][O:28]3)=[CH:37][CH:36]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1CC[C@@H](Nc2ccc(F)cc2)[C@@]2(O)CCCO[C@H]12)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OC[C@@H]1CC[C@@H](Nc2ccc(F)cc2)[C@]2(O)CCCO[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 68 mg (4aS,5R,8S,8aR)-8-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-[(4-fluorophenyl)amino]hexahydro-2H-chromen-4a(5H)-ol in 4 mL tetrabutylammonium fluoride solution (2.0 M in THF) and stirred overnight at RT. Excess solvent was removed using a rotovap, then the residue was diluted with CH2Cl2, added to water, and extracted with CH2Cl2. The crude extract was dried over Na2SO4, filtered, concentrated, then purified on silica gel to provide the title compound. 1H NMR (500 MHz, CDCl3) δ=1.32-1.39 (m, 1H), 1.55-1.90 (m, 5H), 2.06-2.16 (m, 2H), 2.24-2.28 (m, 1H), 2.34-2.46 (m, 1H). 3.46 (s, 1H), 3.49-3.56 (m, 2H), 3.68-3.75 (m, 1H), 3.77-3.82 (m, 1H), 4.12 (dd, J1=11.4 Hz, J2=6.0 Hz, 1H), 4.64 (d, J=11.2 Hz), 6.50-6.56 (m, 2H), 6.85-6.90 (m, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.FC(F)(F)S(O[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][C@H:21]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][O:23]2)(=O)=O>>[CH2:36]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:21]1[CH2:20][C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:23][CH2:22]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cn1
Yield: 84 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 84% yield, starting from 2-methoxy-5-pyridineboronic acid (1.7 equiv) and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate; MS (ESI) m/z 437[M+H+].
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][C:21](=[O:23])[O:20][N:19]=2)=[C:14]([O:24][CH3:25])[CH:13]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=O)=O>CN(C)C=O>[CH3:25][O:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10][C:9]2[S:8][C:7]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=3)=[N:6][C:5]=2[CH2:4][CH2:3][CH2:2][S:44][CH3:43])[CH:17]=[CH:16][C:15]=1[C:18]1[NH:22][C:21](=[O:23])[O:20][N:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCO)ccc1-c1noc(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCSC)ccc1-c1noc(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 100 mg of 3-{4-[4-(3-hydroxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one in 1 mL of dimethylformamide at 0° C. were added 0.077 mL of triethylamine and 0.015 mL of methanesulfonyl chloride. The resulting mixture was stirred at 0° C. for 30 minutes and then concentrated under reduced pressure. The product was dissolved in 3 mL of dimethylformamide. To the resulting solution were added 5.5 mg of sodium methanethiolate and 13 mg of potassium iodide. The reaction mixture was heated for 10 minutes to 90° C. under microwave irradiation in a sealed tube. It was then concentrated under reduced pressure, taken into dichloromethane, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 20 mg of 3-{2-methoxy-4-[4-(3-methylsulfanyl-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=O)[CH2:5][C:4](=[O:9])[CH2:3]1.[NH3:10]>C1C=CC=CC=1>[NH2:10][C:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][C:4](=[O:9])[CH:5]=1
Reactant: N
Reactant: CC1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CC1CC(=O)C=C(N)C1
Temperature: 0 °C

Procedure:
5-Methyl-1,3-cyclohexanedione (40 g, 0.32 mol) was dissolved in 500 ml of benzene at 70° C. The solution was heated at reflux for 2 hours, during which NH3 was bubbled through the reaction mixture and formed H2O was collected in a Dean-Stark trap. The mixture was then cooled to 0° C. and title product recovered by filtration, 39.8 g, m.p. 165-169° C.