Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[F:17][C:18]([F:27])([F:28])[O:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([NH:1][C:12](=[O:15])[CH2:13][CH3:14])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(C(=O)O)cc1N
Product: CCC(=O)Nc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)ccc1C

Procedure:
Compound 69 is synthesized following a similar method as in Example 1 and using 3-amino-4-methylbenzoic acid, propionyl chloride and 4-trifluoromethoxyaniline as materials. Total yield of the two steps: 49%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[Cl:19])[CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+]>C1COCC1.CO.[Zn]>[Cl:19][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:14][C:13]([F:15])=[C:12]([NH2:16])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Chloro-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine (1.31 g, 4.31 mmol) was dissolved in THF (108 mL) and MeOH (108 mL). Ammonium chloride (2.31 g, 43.1 mmol) was added, followed by zinc dust (2.82 g, 43.1 mmol). The reaction mixture was stirred at RT for 1 h. The solids were filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to yield 5-chloro-4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine as a brown solid which was used without purification assuming a 100% yield. MS (ESI) m/z: 273.0 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(O[K])(C)(C)C.F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].CCOC(C)=O>CS(C)=O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: c1c[nH]cn1
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of imidazole (0.997 g, 14.65 mmol) and tert-BuOK (1.722 g, 15.35 mmol) was put under Ar in a 100 mL and dissolved in dry DMSO (15 mL) to give a colorless solution. After 5 min, 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (2.04 mL, 14.58 mmol) was added within 30 s, immediately leading to a darkening of the rm to black. A temperature rise was also noted. The black solution was stirred at RT for 20 min. Ice water (60 mL) and EtOAc (50 mL) were added, the organic layer was isolated, and the aqueous phase was extracted twice with 20 mL EtOAc. The organic layer was washed with H2O (2×30 mL), brine, dried, filtered and evaporated to give the title compound as an orange oil. Yield: 3.66 g (97%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]=O.O=P(Cl)(Cl)Cl.C([O:18][C:19](=[O:22])[CH2:20][SH:21])C.[OH-].[Na+].[CH2:25](O)C>O.CN(C=O)C>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:25]=[C:20]([C:19]([OH:18])=[O:22])[S:21][CH:8]=1
Reactant: CCO
Reactant: Cc1ccccc1CC=O
Reactant: CCOC(=O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1csc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
At 5° C., o-tolyl-acetaldehyde (3.50 g, 29 mmol) is added to a mixture of POCl3 (7.5 mL, 93 mmol) and DMF (8 mL). The mixture is stirred at 70° C. for 3 h before the reaction is quenched by adding water/ice and NaOAc (17 g) and extracted with EA (2×150 mL). The solvent of the organic extract is evaporated and the product is purified by CC on silica gel eluting with heptane:EA 9:1. The resulting oil (2.5 g) is dissolved in ethanol (5 mL) and then added dropwise to a freshly prepared solution of Na (318 mg, 13.8 mmol) and ethyl-2-mercaptoacetate (1.64 g, 13.6 mmol) in ethanol (15 mL). The reaction mixture is stirred at rt for 16 h, then at 70° C. for 2 h. 3 M aq. NaOH (15 mL) is added and the mixture is stirred at 70° C. for 2 h. The mixture is cooled to rt, diluted with water and extracted with DCM. The aqueous phase is acidified with aq. HCl and extracted with EA. The organic extract is dried over MgSO4 and the solvent is evaporated to give crude 4-o-tolyl-thiophene-2-carboxylic acid (790 mg) as a brown solid; LC-MS: tR=0.91 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]2[CH2:15][CH2:14][CH:13](Br)[C:12](=O)[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2].[C:20]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:27][CH2:28][NH:29][C:30]([NH2:32])=[S:31])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(#N)C.C(N(CC)CC)C>O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][C:13]1[S:31][C:30]([NH:29][CH2:28][CH2:27][CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:32][C:12]=12)[CH3:2]
Reactant: NC(=S)NCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCC(Br)C2=O
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cccc2c1CCc1sc(NCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 38.3 %

Procedure:
To a mixture of ethyl[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate (1.20 g, 3.67 mmol), N-(3,3-diphenylpropyl)thiourea (1.10 g, 4.04 mmol), and acetonitrile (30 mL) was added triethylamine (0.56 mL, 4.04 mmol), and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N-hydrochloric acid, saturated aqueous sodium chloride solution, and water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate=5:1) to provide 700 mg of ethyl[[2-(3,3-diphenylpropyl)amino-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of this compound in acetic acid (10 mL) was added concentrated hydrochloric acid (5 mL) and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to provide 500 mg of the title compound. Yield 17%.
Reaction SMILES: [C:1]12([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=4)[CH2:14][C:13]3=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[Na+].[Na+].[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>C1(C)C=CC=CC=1.C(O)C.O.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]12([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:34]5[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=5)[CH:19]=4)[CH2:14][C:13]3=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C1Cc2ccc(Br)cc2N1CC12CC3CC(CC(C3)C1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-c2ccc3c(c2)N(CC24CC5CC(CC(C5)C2)C4)C(=O)C3)cc1
Temperature: 100 °C
Yield: 30.3 %

Procedure:
To a solution of 1-adamantan-1-ylmethyl-6-bromo-1,3-dihydro-indol-2-one (1.85 g, 5.13 mmol) in toluene (23 ml) and ethanol (21 ml) were added tetrakis(triphenylphosphine)palladium (0.60 g, 0.513 mmol), sodium carbonate (1.09 g, 10.27 mmol) in water (11 ml) and solid 4-cyanophenylboronic acid (1.51 g, 10.27 mmol). The mixture was heated at 100° C. overnight. The reaction mixture was partitioned between chloroform and aqueous saturated potassium carbonate (50 ml). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give the crude product. This was chromatographed on flash silica gel eluting with a 15% ethyl acetate in hexane to give the title compound of 9C as a white solid (0.594 g, 30.3% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:14]([OH:16])=O.[N:21]1([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:14]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:29][CH:30]=1)=[O:16]
Reactant: Nc1ccc(CCN2CCCC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(CCN3CCCC3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIEA (4734, 2.72 mmol) was added into a solution of 3-bromo-4-methylbenzoic acid (189 mL, 0.881 mmol), 4-(2-(pyrrolidin-1-yl)ethyl)benzenamine (140 mg, 0.734 mmol), BOP (487 mg, 1.01 mmol) in DMF. The reaction mixture was stirred at rt under argon atmosphere overnight. The reaction mixture was diluted with AcOEt, and then washed with 1N NaOH aqueous solution three times. Organic phase was dried with anhydrous Na2SO4, and then evaporated to remove organic solvents. The obtained residue was further dried under high vacuum overnight to give crude product, which was used directly for the next step synthesis without further purification. MS (ESI+) m/z 387.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[Cl:11]N1C(=O)CCC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH2:6])=[C:7]([Cl:11])[C:8]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(Br)c(Cl)cc1N
Product: Cc1cc(Br)c(Cl)c(Cl)c1N

Procedure:
This material was prepared from 4-bromo-5-chloro-2-methyl aniline by chlorination with N-chlorosuccinimide. The product was isolated as a solid, mp 66°-68° C. The product was characterized by IR and 1H NMR spectroscopy and combustion analysis.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][Br:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br-:12].[C:1]([O:9][CH2:10][CH2:11][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCBr)c1ccccc1
Reactant: c1ccncc1
Solvent: CC#N
Product: O=C(OCC[n+]1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A solution of 50.0 grams (0.218 mol) of 2-bromoethyl benzoate, 17.27 grams (0.218 mol) of pyridine and 135 milliters of acetonitrile was heated at reflux for 17.75 hours and cooled. Solid crystallized and was collected, washed with acetonitrile, then with ether and dried. The yield of product was 48.5 grams (72.19% of theory); mp=162°-164° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:10]1([S:16][C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cc(C)cc(Sc2ccccc2)c1
Yield: 91.4 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), thiophenol (103 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3,5-dimethylphenyl phenyl sulfide (196 mg, 92% yield) as colorless liquid. Column chromatography solvent (hexane). Rf=0.5 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.19-7.29 (m, 5 H), 6.97 (s, 2 H), 6.87 (s, 1 H). MS (EI) m/z (relative intensity) 214 (100), 137 (30).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=C=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>[O-]CC.[Na+].O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(O)cc1
Temperature: 30 °C
Reaction time: 0.4 h

Procedure:
p-Hydroxybenzoic acid (59.05 grams, 0.4275 mole), sodium ethoxide catalyst (0.133 gram, 0.225% wt. of the p-hydroxybenzoic acid used) and N,N'-dimethylacetamide solvent (404 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at 80° C. p-Nitrophenylisocyanate (73.85 grams, 0.450 mole) is initially added in an aliquot of 25.00 grams, followed by 25.00 and 23.85 gram aliquots eleven then nine minutes later, respectively, and so as to maintain a 80° to 82° C. reaction temperature. After the last aliquot of p-nitrophenylisocyanate is added, heating of the reactor commenced and a 160° C. reaction temperature is achieved 24 minutes later. After three hours at the 160° C. reaction temperature, the reactor is cooled to 30° C. then the contents poured into one gallon of deionized water. A precipitated yellow powder is recovered via filtration of the aqueous slurry then dissolved into 1900 milliliters of boiling methanol and refluxed therein (65 ° C.). After cooling the methanol solution to 5° C. and maintaining therein for twelve hours, a first crop of pale yellow colored crystalline product is filtered off and dried at 110° C. under vacuum to a constant weight of 92.5 grams (79.6% isolated yield). No attempt was made to recover a second crop of crystalline product from the mother liquor. Fourier transform infrared spectrophotometric analysis of a nujol mull of a portion of the product on a sodium chloride plate revealed the presence of the expected secondary amide N--H stretching (solid state) at 3385 cm-1 (sharp), the secondary amide carbonyl stretching (solid state) at 1655 cm-1 (sharp), the hydroxyl group O--H stretching centered at 3232 cm-1 (broad) and the conjugated nitro group absorbances at 1537 and 1339 cm-1 (sharp). Proton magnetic resonance spectroscopy (250 MHz) further confirmed the product structure as 4-hydroxy-4'-nitrobenzanilide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(N(CC)CC)C.C([Cl:36])(=O)OCC.[O:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][NH2:46])[CH2:39][CH2:38]1>C1COCC1>[ClH:36].[ClH:36].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:46][CH2:45][CH2:44][CH2:43][N:40]3[CH2:41][CH2:42][O:37][CH2:38][CH2:39]3)=[O:20])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: NCCCN1CCOCC1
Reactant: Cc1csc(Nc2cc(Oc3cccc(C(=O)O)c3)ccn2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3cccc(C(=O)NCCCN4CCOCC4)c3)ccn2)n1
Product: Cl
Yield: 106 %

Procedure:
Using the method of Example 32, 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid (0.1 g, 0.3055 mmol), triethylamine (0.2129 mL, 1.527 mmol), ethyl carbonochloridate (0.03359 mL, 0.3513 mmol), and 3-morpholinopropan-1-amine (0.1339 mL, 0.9164 mmol) were reacted in THF (2 mL) to provide 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)-N-(3-morpholinopropyl)benzamide dihydrochloride (0.098 g, 60.33% yield) as off white solid. 1H NMR (CDCl3) δ 8.52 (s, 1H), 8.19 (d, 1H), 7.91 (d, 1H), 7.74 (s, 1H), 7.54 (t, 1H), 7.24 (d, 1H), 6.82 (dd, 1H), 6.41 (s, 1H), 4.26 (m, 2H), 3.99 (m, 2H), 3.65 (m, 2H), 3.52 (m, 2H), 3.19 (t, 2H), 2.89 (m, 2H), 2.41 (d, 3H), 2.26 (m, 2H); Mass spectrum (esi) m/z=454 (100) (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.C([Li])CCC.O1CCCC1.Br[CH2:27][CH2:28][CH2:29][N:30]1[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]1[CH3:36]>C(OCC)C.CCCCCC>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:27][CH2:28][CH2:29][N:30]2[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]2[CH3:36])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: Cc1ccc(C)n1CCCBr
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(CCCCn2c(C)ccc2C)nc(-n2c(C)ccc2C)c1
Temperature: -17.5 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A solution of 297 mg (1.49 mmol) of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (from Example 53, Step A) in 1.5 mL of ethyl ether was added to a -20° C. solution prepared from 3.0 mL of ethyl ether and 1.2 mL (1.7 mmol) of 1.4 M n-butyllithium in hexane. The mixture was stirred for 1 h at -20 to -15° C. with the formation of a preciptate. Tetrahydrofuran (1.0 mL) was added, the resulting orange-red solution was cooled to .BECAUSE.45° C., and 400 mg (1.85 mmol) of 1-(3-bromopropyl)-2,5-dimethylpyrrole (S. P. Bruekelman, S. E. Leach, G. D. Meakins, and M. D. Tirel, J. Chem. Soc., Perkin Trans. 1, 1984, 2801-7) was added in one portion. The mixture was allowed to warm to 10° C. over 1.75 h, quenched with 10 mL of saturated aqueous ammonium chloride, and extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of saturated aqueous sodium chloride, dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on 50 g of silica gel, eluting with 1.2 L of 5% ethyl acetate in hexane to give 402 mg (80% yield) of 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2,5-dimethylpyrrol-1-yl)butyl)pyridine as an almost colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1C(O)=O.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[NH2:28][C:29]1[C:30]([OH:40])=[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])[C:32]([Cl:35])=[CH:33][CH:34]=1.C[N:42]([CH:44]=[O:45])C>>[Cl:35][C:32]1[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])=[C:30]([OH:40])[C:29]([NH:28][C:44]([NH:42][CH:3]2[C:4]([CH3:5])([CH3:6])[C:2]2([CH3:1])[CH3:10])=[O:45])=[CH:34][CH:33]=1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: CN(C)C=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: CC1(C)C(NC(=O)Nc2ccc(Cl)c(S(N)(=O)=O)c2O)C1(C)C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2,2,3,3-tetramethyl-cyclopropanecarboxylic acid (0.142 mL, 1.0 mmol) in DMF (0.5 mL) was added DPPA (0.25 mL, 1.2 mmol) and TEA (0.25 mL, 1.8 mmol) and the reaction heated at 80° C. After 18 hrs, 3-Amino-6-chloro-2-hydroxy-benzenesulfonamide (1.0 mmol) was added and the reaction heated at 80° C. After 18 hrs, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate, and concentraed under reduced pressure. The crude residue was purified via HPLC to give 96 mg of 6-Chloro-2-hydroxy-3-[3-(2,2,3,3-tetrmethyl-cyclopropyl)-ureido]-benzenesulfonamide. LC-MS (m/z) 347 (M+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][C:27](Cl)=[CH:26][CH:25]=4)([CH3:23])[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:41]C1C=CC(C2(C)OCCNC2)=CC=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][C:19]([CH3:23])([C:24]4[CH:29]=[CH:28][C:27]([CH3:41])=[CH:26][CH:25]=4)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(C2(C)CNCCO2)cc1
Reactant: Cc1cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1ccc(C2(C)CN(c3nc4cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c5ccc(Cl)cc5)c4s3)CCO2)cc1

Procedure:
(2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-methyl-2-p-tolylmorpholino)benzo[d]thiazol-6-yl)acetic acid was prepared using the similar procedure as (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-2-methylmorpholino)-5-methylbenzo[d]thiazol-6-yl)acetic acid except 2-(4-methylphenyl)-2-methylmorpholine was used instead of 2-(4-chlorophenyl)-2-methylmorpholine. LCMS-ESI+: calc'd for C32H35ClN2O4S: 579.2, 581.2 (M+H+); found: 579.4, 581.3 (M+H+). 1H-NMR: 400 MHz, (CD3OD) δ: 7.62 (m, 1H), 7.47-7.54 (m, 3H), 7.32 (m, 3H), 7.14 (m, 2H), 5.14 (s, 1H), 4.31 (t, J=12.8 Hz, 1H), 3.80 (m, 1H), 3.64 (m, 1H), 3.40-3.51 (m, 3H), 2.50 (s, 3H), 2.28 (s, 3H), 1.44 (s, 3H), 0.95 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15](O)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1.C(Cl)(=O)C(Cl)=O.[CH3:30][NH:31][C:32]([NH2:34])=[O:33].N1C=CC=CC=1.Cl>FC1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:34][C:32]([NH:31][CH3:30])=[O:33])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1
Reactant: CNC(N)=O
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: Fc1ccccc1
Solvent: CCOC(C)=O
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
A solution of 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionic acid (303 mg, 0.9 mmol) in fluorobenzene (1 mL) and NN-dimethylformamide (3 μL) at 25° C. was treated dropwise with oxalyl chloride (97 μL, 1.09 mmol) over 2-3 min. The clear solution was stirred at 25° C. for 1 h and then treated with methyl urea (201 mg, 2.72 mmol). The resulting suspension was heated at 70° C. (bath temperature) for 10 min and then treated with pyridine (146.6 μL, 1.81 mmol). The reaction mixture was then stirred at 70° C. for 20 h. The reaction mixture was then cooled to 25° C. and diluted with ethyl acetate (30 mL) and a 3N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded 1-{2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionyl}-3-methyl-urea (110 mg, 31%) as a white solid: mp 185-186° C. EI-HRMS m/e calcd for C18H23ClN6O2 (M+H)+ 391.1649, found 391.1659.