Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32]2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:34]=[C:33]4[C:29]([CH:30]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32]4)=[CH:28][CH:27]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1cc2ccc(N)cc2[nH]1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCOC(=O)c1cc2ccc(NC(=O)C(CC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 56 mg (0.28 mmol, 1.1 eq.) of ethyl 6-amino-1H-indole-2-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 75 mg (55% of theory)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[S:9]1(=[O:15])(=[O:14])[CH2:13][CH2:12][CH2:11][NH:10]1>CO>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][N:10]2[CH2:11][CH2:12][CH2:13][S:9]2(=[O:15])=[O:14])=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: O=S1(=O)CCCN1
Solvent: CO
Product: O=S1(=O)CCCN1CCc1ccncc1
Reaction time: 7 h
Yield: 74.4 %

Procedure:
A mixture of 4-vinylpyridine (324 g), isothiazolidine-1,1-dioxide (373 g), and "Triton B" solution (129 ml, 40% w/v in methanol) was heated in D.M.F. at 50°-55° for 7 hours. The reaction mixture was then concentrated under vacuum, water (2.52 liters) was added, and the product was extracted into CH2Cl2 (3×1.87 liters). The combined methylene chloride extracts were washed with water and then evaporated to dryness. The residue was dissolved in ethyl acetate (1.3 liters) at 35° and hexane (0.87 liters) was added over 10 minutes. The resulting crystalline product was granulated at -5 to 0° for 4 hours, filtered, washed with hexane (0.37 liters) and dried in vacuum at 25°, to give 2-[2-(4-pyridyl)ethyl]isothiazolidine-1,1-dioxide (518 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:31]([C:2]1[CH:3]=[C:4]([CH2:5][N:6]2[C:10]([CH3:11])=[N:9][C:8]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=4)[N:13]=3)=[N:7]2)[CH:28]=[CH:29][CH:30]=1)=[CH2:32]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 110 °C

Procedure:
To a mixture of 5-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Example 11, Step 1; 200 mg, 0.42 mmol), tributyl(vinyl)stannane (159 mg, 0.50 mmol) and K2CO3 (174 mg, 1.26 mmol) in 1,4-dioxane (5 mL), was added Pd(PPh4)3 (28 mg, 0.025 mmol). The reaction mixture was heated in a sealed vial at 110° C. under inert atmosphere for 12 h, cooled to RT, diluted with H2O (30 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by prep-HPLC to give the title compound as a white solid; MS (ES+) C21H16F3N5O2 requires: 427. found: 428 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ 8.22 (d, J=9 Hz, 2H), 7.61 (d, J=9 Hz, 2H), 7.48 (d, J=7 Hz, 1H), 7.43 (s, 1H), 7.38 (m, 1H), 7.21 (d, J=7 Hz, 1H), 6.76 (m, 1H), 5.87 (d, J=17.5 Hz, 1H), 5.57 (s, 2H), 5.31 (d, J=11.5 Hz, 1H), 2.60 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.I[C:30]1[CH:31]=[N:32][NH:33][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)=[CH:25][CH:26]=1
Reactant: Ic1cn[nH]c1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4cn[nH]c4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and 4-iodo-1H-pyrazole.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4]1.[ClH:11]>C1COCC1.CSC>[ClH:11].[F:1][C:2]([F:10])([F:9])[C:3]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4]1
Reactant: N#CCC1(C(F)(F)F)CC1
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: NCCC1(C(F)(F)F)CC1
Temperature: 0 °C
Yield: 40 %

Procedure:
Treat a solution of 2-(1-(trifluoromethyl)cyclopropyl)acetonitrile (2.2 g, 14.7 mmol) in THF (60 mL), under N2, with BH3 (10 M in dimethyl sulfide, 3 mL, 30 mmol) and heat at 70° C. overnight. Cool the mixture to 0° C., treat dropwise with methanolic HCl, concentrate to dryness, dissolve in MeOH, re-concentrate and treat the residue with EtOAc. Collect the solids via filtration and dry to afford the title compound (1.1 g, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 3H), 2.87 (t, J=8.4 Hz, 2H), 1.90-1.86 (m, 2H), 0.96-0.93 (m, 2H), 0.82-0.81 (m, 2H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(Br)s1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)s1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A mixture of compound 1021 (5.0 g, 22.6 mmol), biphenyl-4-ylboronic acid (5.4 g, 27.1 mmol), sodium carbonate (5.9 g, 56.5 mmol), tetrakis(triphenylphosphine)palladium(0) (2.65 g, 2.3 mmol), toluene (200 mL), ethanol (100 mL) and water (50 mL) was heated to reflux for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, and extracted with dichloromethane (2×250 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography with silica gel (5% EtOAc in hexane) to give compound 1022 (5.0 g). 1H NMR (CDCl3, 300 MHz) δ 3.92 (s, 3H), 7.32-7.49 (m, 4H), 7.62-7.80 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)C(=O)CNC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)C(C)C
Yield: 90.2 %

Procedure:
5.6 g of N-(4-fluorobenzoyl)isobutyrylmethylamine, 1.2 g of 61% sodium hydride and 4.61 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(5). 7.0 g of ethyl 3-(4-fluorobenzoylamino)-3-isobutyrylpropionate are thereby obtained as oil. Yield: 90.0%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=[C:20]=[O:21]>C1COCC1.C(Cl)Cl>[NH2:17][C:16]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[O:21])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)ccnc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(-c3ccnc4c3c(N)nn4C)cc2)c1
Yield: 46.2 %

Procedure:
A solution of Example 40 (87 mg, 0.36 mml) and 1-isocyanato-3-methylbenzene (0.046 mL, 0.36 mmol) in THF (3 mL), CH2Cl2 (3 mL) was stirred at room temperature for 5 h. The resulting precipitate was filtered off and purified via HPLC on an Agilent Zorbax Stablebond C-18 (7 micron particle size) preparative column using a solvent gradient of 20% to 100% acetonitrile in 0.1% aqueous TFA at a flow rate of 15 ml/min over 50 min, to give the 62 mg of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 3.83 (s, 3H) 6.81 (d, J=7.46 Hz, 1H) 6.92 (d, J=4.75 Hz, 1H) 7.17 (t, J=7.80 Hz, 1H) 7.26 (d, J=8.48 Hz, 1H) 7.32 (s, 1H) 7.53 (d, J=8.81 Hz, 2H) 7.65 (d, J=8.82 Hz, 2H) 8.40 (d, J=4.75 Hz, 1H) 8.67 (s, 1H) 8.90 (s, 1H). MS (ESI(+)) m/e 373 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH:26]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]([O:29][CH3:30])=[O:28])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: COC(=O)C(Br)c1ccccc1
Product: COC(=O)C(Oc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)C(C)(C)O2)c1ccccc1
Yield: 82 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and methyl α-bromophenylacetate, the title compound was obtained in the same manner as in Example 1. This was oily.
Reaction SMILES: OO.C([OH:7])(C)(C)C.C=CCCCCCC.[O:16]([CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][OH:20])O>[W].C(OC)(C)(C)C>[O:20]([CH2:19][CH:18]([OH:16])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[OH:7]
Reactant: CC(C)(C)O
Reactant: CCCCCCC(CO)OO
Agent: [W]
Agent: OO
Solvent: C=CCCCCCC
Solvent: COC(C)(C)C
Product: CCCCCCC(O)COO
Temperature: 50 °C
Yield: 42 %

Procedure:
To a 50 mL flask equipped with a magnetic stirrer and a refluxing condensing tube were added 300 mg of the tungsten-containing mesoporous silicate prepared in Example 2, 760 mg of 60% by weight aqueous hydrogen peroxide solution, 3 g of tert-butanol and 500 mg of 1-octene, and the mixture was stirred and maintained at an inner temperature of 50° C. for 16 hours to react these materials. To the resulting reaction mixture was added 5 g of methyl tert-butyl ether, and the mixture was stirred, and allowed to stand. The supernatant organic layer was analyzed by LC, and it was found that 2-hydroperoxy-1-hydroxyoctane and 1-hydroperoxy-2-hydroxyoctane were produced. When the organic layer was analyzed by GC, 2-hydroperoxy-1-hydroxyoctane and 1-hydroperoxy-2-hydroxyoctane were thermally decomposed at an injection inlet, and detected as 1-heptanal. Then, the yield of 1-heptanal was determined by GC analysis (internal standard method), and this was regarded as the yield of 2-hydroperoxy-1-hydroxyoctane and 1-hydroperoxy-2-hydroxyoctane. Yield: 42%
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]([CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH:19]=[CH2:20]>C(Cl)(Cl)Cl>[CH2:18]([O:17][CH2:16][CH2:15][CH2:14][C:13](=[O:12])[CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[CH:19]1[O:9][CH2:20]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOCCCC(=O)CCC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)CCC(=O)CCCOCC1CO1
Yield: 78.8 %

Procedure:
A 1000-ml round bottom flask equipped with a magnetic stirrer and a dropping funnel was charged with 130 g (0.38 mol) of 50-% m-chloroperbenzoic acid and 450 ml of chloroform. The dropping funnel was charged with 36.10 g (0.18 mol) of allyl 4,7-dioxooctyl ether. The contents of the dropping funnel were added drop-wise to the flask within 1 hour. During the addition the contents of the flask were stirred and kept at about 0° C. by cooling with an external cooling bath. After additional stirring overnight, during which the mixture was allowed to adopt room temperature, the mixture was filtered. The filtrate was extracted with an equal volume of 10-% aqueous sodium hydroxide and with an equal volume of water, dried over magnesium sulphate and evaporated to dryness, leaving 30.4 g of 4,7-dioxooctyl glycidyl ether as a colourless oil. The structure was confirmed by 1H-NMR spectroscopy. The signals were assigned to the underlined hydrogen atoms (shifts relative to TMS, chloroform-d1 solvent): ##STR9##
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8](C(O)=O)=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].OC1C=C(C=CC=1C)[C:19]([OH:21])=[O:20]>>[CH:1]([O:4][C:5]1[CH:13]=[C:12]([CH:8]=[CH:7][C:6]=1[CH3:14])[C:19]([OH:21])=[O:20])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Product: Cc1ccc(C(=O)O)cc1OC(C)C

Procedure:
3-Isopropoxy-4-methyl-benzoic acid (1.70 g) is prepared in analogy to 4-isopropoxy-3-methyl-benzoic acid starting from 3-hydroxy-4-methyl-benzoic acid (2.00 g); LC-MS: tR=0.91 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]1([N:25]2[C:29]([C:30]([F:33])([F:32])[F:31])=[C:28]([C:34](Cl)=[O:35])[CH:27]=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:34]([C:28]4[CH:27]=[N:26][N:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[C:29]=4[C:30]([F:32])([F:33])[F:31])=[O:35])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1cnn(-c2ccccc2)c1C(F)(F)F
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cnn(-c2ccccc2)c1C(F)(F)F
Yield: 28 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride to afford the title compound (28 mg, 28%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.92 (d, 1H, Harom, J=8.0 Hz), 7.43 (t, 1H, Harom, J=8.0 Hz), 7.51-7.63 (m, 7H, Harom), 7.81 (d, 1H, HPy,6, J=6.0 Hz), 8.29 (s, 1H, Hpyrrazole), 10.63 (s, 1H, NHamide), 11.19 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C23H16N6O3F3: 481.1236; found: 481.1229.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:18](=[O:29])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.S(O)(O)(=O)=O.CS[C:37](=[NH:39])[NH2:38].CSC(=N)N.C(N(CC)CC)C.O>CN(C=O)C>[ClH:2].[C:37]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][N:19]2[CH2:20][CH2:21][N:16]([S:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=4)[CH:9]=3)(=[O:15])=[O:14])[CH2:17][C:18]2=[O:29])[CH2:24][CH2:25]1)(=[NH:38])[NH2:39]
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1CC1CCNCC1
Reactant: CSC(=N)N
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)N1CCC(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 127.4 %

Procedure:
To a solution of 4-(6-chloronaphthalene-2-sulfonyl)-1-(4-piperidylmethyl)-2-piperazinone hydrochloride (230 mg) in DMF (10 ml) were added S-methylisothiourea hemisulfate (348 mg), triethylamine (0.418 ml) and water (2 ml), and the mixture was stirred at 50° C. overnight. To the mixture was added S-methylisothiourea hemisulfate (348 mg) and triethylamine (0.418 ml), and the mixture was additionally stirred at 50° C. overnight. The solvent was concentrated and purified with CHP20 column chromatography (water:acetonitrile:1 N hydrochloric acid=70:30:1) to give colorless amorphous of the title compound (160 mg).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([CH2:25][C:26]2[CH:34]=[C:33]([Cl:35])[C:32]([OH:36])=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:44][C:45]([O:47]C)=[O:46]>CN(C=O)C.CCOC(C)=O>[C:1]1([S:7]([NH:10][CH:11]([C:12](=[O:13])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][C:26]2[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH2:44][C:45]([OH:47])=[O:46])=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CBr
Reactant: O=C(NCCCCc1ccccc1)C(Cc1cc(Cl)c(O)c2[nH]ncc12)NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)COc1c(Cl)cc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2cn[nH]c12
Reaction time: 36 h

Procedure:
2-Benzenesulfonylamino-3-(6-chloro-7-hydroxy-1H-indazol-4-yl)-N-(4-phenyl-butyl)-propionamide (30 mg, 0.057 mmol) is dissolved in DMF (1 mL) and K2CO3 is added followed by a slight excess of methyl bromoacetate (11 mg, 0.072 mmol). The reaction is allowed to stir for 36 h. The reaction is worked-up by diluting with EtOAc and washing with NH4Cl, 0.5 N HCl, water and brine. The solution is dried with MgSO4 and concentrated to provide a mixture of the intermediate ester and desired acid product as observed by LC/MS. The acid is purified by chromatography using a 10 g C18 sep-pak column (CH3CN/H2O) to provide {4-[2-benzenesulfonylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-6-chloro-1H-indazol-7-yloxy}-acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.17 (d, 1H), 8.29 (bs, 1H), 7.94 (dd, 1H), 7.46 (d, 2H), 7.42 (dd, 1H), 7.28–7.24 (m, 4H), 7.16–7.14 (m, 3H), 6.84 (s, 1H), 4.59 (bs, 2H), 4.19–4.15 (m, 1H), 4.01–3.95 (m, 1H), 3.03–2.97 (m, 1H), 2.90–2.79 (m, 3H), 2.50 (obs, 2H), 1.43–1.38 (m, 2H), 1.22–1.17 (m, 2H); MS (ESI+) m/z 585 (M+H).
Reaction SMILES: C[C@@H](PC)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:53]=[CH:54][CH:55]=1)[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=2)[CH2:39][CH2:38][C:37]=1[NH:48][C:49](=[O:52])[CH2:50][CH3:51].[H][H]>[Rh+].ClC1CCCCC=CC=1.CO>[Cl:31][C:32]1[CH:33]=[C:34]([CH:53]=[CH:54][CH:55]=1)[CH2:35][C@@H:36]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=2)[CH2:39][CH2:38][C@@H:37]1[NH:48][C:49](=[O:52])[CH2:50][CH3:51]
Reactant: [H][H]
Reactant: CCC(=O)NC1=C(Cc2cccc(Cl)c2)c2cc(OC)ccc2CC1
Agent: [Rh+]
Agent: CP[C@H](C)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CO
Product: CCC(=O)N[C@H]1CCc2ccc(OC)cc2[C@H]1Cc1cccc(Cl)c1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (29.2 mg, 0.118 mmol of Rh), Josiphos SL-J216-2 (79.1 mg, 0.123 mmol), and N-(1-(3-chlorobenzyl)-7-methoxy-3,4-dihydronaphthalen-2-yl)propionamide (43.30 g, 122 mmol) were combined in a metal reactor, and the vessel was inerted with argon. Degassed methanol (435 ml) was added, then the mixture was agitated under argon at 45° C. for 20 min. The reactor was pressurized to 60 psig with hydrogen and agitated at 60° C. for 16 hrs. HPLC analysis showed complete conversion and 95.2% ee. The mixture was concentrated, and the resulting solid was slurried in heptane and dried in vacuo at 40° C. to yield 42.8 g (yield: 95%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH3:17]>ClCCl>[CH:5]1[C:4]2[C:9](=[CH:10][C:11]3[C:16]([C:3]=2[CH2:2][NH:17][CH2:2][C:3]2[C:16]4[C:11]([CH:10]=[C:9]5[C:4]=2[CH:5]=[CH:6][CH:7]=[CH:8]5)=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: N
Solvent: ClCCl
Product: c1ccc2c(CNCc3c4ccccc4cc4ccccc34)c3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
A solution of 9-chloromethyl anthracene (278 mgr, 1.22 mmoles) in dichloromethane (1.5 ml) was bubbled with gaseous ammonia for 10 minutes. More dichloromethane was added, the reaction vessel was tightly closed and the reaction mixture was stirred for two days, at room temperature. Concentration in vacuo and purification of the crude product by flash chromatography afforded 30 mgr (14%) of N,N-di-(9-anthrylmethyl)-amine as yellow solid. 1H NMR (250 MHz, CDCl3): δ 8.48 (2H, s), 8.25-8.10 (4H, m), 8.09-7.80 (4H, m), 7.55-7.25 (8H, m), 4.95 (4H, s), 1.98 (NH, broad) ppm; 13C NMR (62.5 MHz, CDCl3): δ 131.8, 131.3, 130.4, 129.3, 128.4, 126.2, 125.1, 124.2, 45.6 ppm; FTIR: 3317, 3052, 2919, 2846, 1938, 1726, 1620, 1448, 1096, 1030, 891, 738 cm−1. HRMS (MALDI) calcd for C30H23N [M+H+] 398.1903, found 398.1917.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:9]1[C:21]2[CH:20]([CH2:22][OH:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCC(=O)O1
Reactant: OCC1c2ccccc2-c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCCC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.6 %

Procedure:
To a solution of glutaric anhydride (1.0 g, 8.76 mmol) and (9H-fluoren-9-yl)methanol (1.56 g, 7.97 mmol) in CH2Cl2 (44 mL) was added DMAP (107 mg, 0.88 mmol) and the mixture was stirred for 20 h at room temperature. The reaction mixture was concentrated, diluted with H2O and saturated NaHCO3 solution and washed with ethyl acetate. The organic layer was extracted with saturated NaHCO3 solution (3×). The combined aqueous layers were acidified to pH=2 with conc. HCl solution, extracted with a 4:1 mixture of CHCl3/i-PrOH (3×′). The organic layers were combined, dried over MgSO4, filtered and concentrated to dryness, yielding acid 151 as a white solid (1.5 g, 61%). 1H NMR (400 MHz, CDCl3) δ 1.95 (quint, J=7.3 Hz, 2H), 2.40 (t, J=7.3 Hz, 2H), 2.47 (t, J=7.3 Hz, 2H), 4.21 (t, J=6.9 Hz, 1H), 4.43 (d, J=7.0 Hz, 2H), 7.32 (dt, J=7.4, 1.1 Hz, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.59 (d, J=7.5 Hz, 2H), 7.78 (d, J=7.5 Hz, 2H).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:20][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH:6]1[CH2:21][CH3:22])[NH:13][C:12](=[O:18])[C:11]([CH3:19])=[CH:10]3)=[N+]=[N-]>[Pd].CN(C)C=O>[NH2:1][CH2:4][CH:5]1[O:20][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH:6]1[CH2:21][CH3:22])[NH:13][C:12](=[O:18])[C:11]([CH3:19])=[CH:10]3
Reactant: CCC1c2cc(C)c3[nH]c(=O)c(C)cc3c2OC1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCC1c2cc(C)c3[nH]c(=O)c(C)cc3c2OC1CN
Yield: 57.4 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 275 using the compound obtained in Example 293 (21 mg, 0. 070 mmol), 10% palladium-on-carbon (10 mg) and dimethylformamide (0.6 ml). 11 mg of the title compound was obtained as colorless crystals (57.4%). The crystals were purified by silica gel column chromatography to obtain the cis- form of the title compound as colorless powdery crystals (mp. 209°-225° C.) and the trans- form of the title compound as colorless powdery crystals (mp. 142°-155° C.).