Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=3)[N:15]=[CH:14][C:13]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:27][C:28]1[C:33](O)=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:29]=1[F:38].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.C(OCC)(=O)C>[F:27][C:28]1[C:33]([O:25][C:24]([C:13]2[CH:14]=[N:15][C:16]3[C:21]([C:12]=2[NH:11][CH2:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)=[O:26])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:29]=1[F:38]
Reactant: COc1ccc(CNc2c(C(=O)O)cnc3ccc(C#N)cc23)cc1Cl
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cnc3ccc(C#N)cc23)cc1Cl
Reaction time: 18 h
Yield: 41 %

Procedure:
To 275 mg (0.748 mmol) of 4-[[(3-chloro-4-methoxyphenyl)-methyl]amino]-6-cyano-3-quinolinecarboxylic acid was added 276 mg (1.50 mmol, 2.0 eq) pentafluorophenol, and the mixture was dispersed in 5 mL anhydrous DMF under nitrogen. To this dispersion was added a solution of 231 mg (1.12 mmol, 1.5 eq) of dicyclohexylcarbodiimide (Aldrich) in 2 mL anhydrous ethyl acetate at RT. The resulting mixture was stirred for 18 hours. The reaction was then diluted with 10 mL EtAc, and the white precipitate was filtered and discarded. The filtrate was concentrated in vacuo, and the residue was triturated with 5% MeOH/95% CH2Cl2 to give 164 mg (0.307 mmol, 41% yield) of the title compound as a white solid: LC/MS: M/Z 534 (M+H) observed, 100% purity; mp: decomposed 215-217° C. LC: 4.15.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]([C:18]2[S:22][C:21]([CH2:23][CH2:24][C:25]([OH:27])=O)=[C:20]([CH3:28])[CH:19]=2)=[O:17])=[CH:13][CH:12]=1)(=[NH:10])[NH2:9].CCN=C=N[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])C.Cl>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:38]([N:39]([C:25](=[O:27])[CH2:24][CH2:23][C:21]1[S:22][C:18]([C:16]([O:15][C:14]2[CH:13]=[CH:12][C:11]([C:8](=[NH:10])[NH2:9])=[CH:30][CH:29]=2)=[O:17])=[CH:19][C:20]=1[CH3:28])[CH2:41][C:3]([OH:5])=[O:4])[CH:37]=[CH2:36]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C(=O)Oc2ccc(C(=N)N)cc2)sc1CCC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(CC(=O)O)C(=O)CCc1sc(C(=O)Oc2ccc(C(=N)N)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 242.4 %

Procedure:
The compound (100 mg, 0.224 mmol) obtained in step 1, M-5 (49.9 mg, 0.291 mmol), and WSC hydrochloride (64.4 mg, 0.336 mmol) were dissolved in pyridine (0.5 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, trifluoroacetic acid (1.0 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (98.5 mg, 0.181 mmol, 81%).
Reaction SMILES: ClC1C2C=CC=CC=2SN=1.[O:11]=[S:12]1(=[O:30])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[N:13]1.Cl.C(OC(=O)CCCN)C.C(N(CC)CC)C>O1CCOCC1>[O:11]=[S:12]1(=[O:30])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[N:13]1
Reactant: CCOC(=O)CCCNC1=NS(=O)(=O)c2ccccc21
Agent: CCOC(=O)CCCN
Agent: Cl
Agent: Clc1nsc2ccccc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)CCCNC1=NS(=O)(=O)c2ccccc21

Procedure:
5.68 g. (28.1 mM) of 3-chloro-1,2-benzisothiazole, 1,1-dioxide (prepared as in Example 1), 4.8 g. (28.1 mM) of ethyl-4-aminobutyrate hydrochloride and 7.84 ml. (56.2 mM) of triethylamine are refluxed in 100 ml. of dioxane for one hour. The solvent is evaporated and the residue refluxed in 1% hydrochloric acid for 2.5 hours. The product crystallizes out overnight at room temperature. The product, 4-[(1,1-dioxo-1,2-benzisothiazol-3-yl)amino]butanoic acid is filtered out, washed with water, and recrystallized from 150 ml. water, yield 4.2 g., m.p. 200°-202°.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:3]1=[O:25].C(N(CC)CC)C.Cl[C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:44]([F:47])([F:46])[F:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1>CCO>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[C:41]([C:44]([F:46])([F:47])[F:45])[CH:42]=4)[N:37]=[CH:36][N:35]=3)[C:3]2=[O:25])[C@H:8]([CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:9]1)([CH3:17])[CH3:16]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 80 °C
Yield: 43.9 %

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (75 mg, 0.14 mmol) in EtOH (2 mL) was added triethylamine (0.12 mL, 0.84 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (39 mg, 0.16 mmol). The mixture was heated at 80° C. for 14 h and then concentrated in vacuo. The residue was purified by HPLC to provide the title compound, (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (35 mg, 44% yield). MS found: (M+H)+=570.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[C:9]1([CH2:15][S:16][CH:17]([C:21](O)=[O:22])[C:18](O)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[OH:22][C:21]1[CH:2]=[C:1]([C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)[O:3][C:18](=[O:19])[C:17]=1[S:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccsc1
Product: O=c1oc(-c2ccsc2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared from the condensation of the trimethylsilyl enol ether of 3-acetylthiophene and the diethyl ester of [(phenylmethyl)thio]propanedioic acid following the same procedure outlined in Method A; m.p. 150-151° C. NMR (DMSO-d6) δ3.98 (s, 2 H), 6.58 (s, 1 H), 7.20 (m, 5 H), 7.48 (m, 1 H), 7.72 (m, 1 H), 8.13 (d, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12]>C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:10]([O:13][CH3:14])[O:11][CH3:12]
Reactant: O=Cc1ccccc1Br
Reactant: COC(OC)OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: COC(OC)c1ccccc1Br
Yield: 94.4 %

Procedure:
To a 500 mL round bottom flask equipped with a reflux condenser were added 2-bromobenzaldehyde (102.5 g, 0.554 mol, Aldrich), trimethyl orthoformate (64.9 mL, 0.594 mol, Aldrich), 10-camphor sulfonic acid (1.25 g, 5.40 mmol, Aldrich), and methanol (100 mL). The reaction was heated at reflux for 14 hrs and concentrated in vacuo. The residue was taken up in 500 mL of ether, washed with 200 mL each of sat. aqueous sodium bicarbonate, water, and sat. aqueous NaCl, dryed over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was distilled through a 27 cm Vigrew column (b.p. 78-82° C./1.2 mmHg), affording a clear colorless oil (120.8 g, 94%). 1H-NMR (300 MHz, CDCl3) δ3.37 (s, 6H), 5.54 (s, 1H), 7.18 (dt, 1H, J=1.7, 8.1 Hz), 7.31 (dt, 1H, J=1.2, 7.5 Hz), 7.54 (dd, 1H, J=1.2, 8.1 Hz), 7.59 (dd, 1H, J=1.7, 7.5 Hz). Mass spectrum (EI+) m/e 230, 232 (M+), 199, 201 (bp).
Reaction SMILES: F[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:4]([CH3:15])[C:5]([C:13]#[N:14])=[C:6]2[C:10]=1[O:9][C:8]([NH:11][CH3:12])=[N:7]2.[CH2:22]([N:24]([CH2:27]C)[CH2:25][CH3:26])C.C[NH:30][C@H:31]1CCN[CH2:32]1>CS(C)=O.ClCCl>[CH3:27][N:24]([CH3:22])[C@H:25]1[CH2:32][CH2:31][N:30]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:4]([CH3:15])[C:5]([C:13]#[N:14])=[C:6]3[C:10]=2[O:9][C:8]([NH:11][CH3:12])=[N:7]3)[CH2:26]1
Reactant: CNc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN[C@H]1CCNC1
Reactant: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CNc1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 150 °C
Reaction time: 4 h
Yield: 30.3 %

Procedure:
7-Fluoro-5-methyl-2-(methylamino)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-131) (0.17 g, 0.60 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (0.17 ml, 1.23 mmol) and (3S)-3-methylaminopyrrolidine (0.16 ml, 1.26 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 10:1), then diisopropyl ether was added, and the insoluble matter was collected by filtration to obtain a beige solid (68.3 mg, 27%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[C:4]([C:18]2[N:19]=[N:20][C:21]([N:24]([CH3:35])[CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)=[CH:22][CH:23]=2)=[C:5]([OH:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15]C)[CH:10]=2)[CH:8]=1.Cl.N1C=CC=CC=1.Cl>CO.CS(C)=O>[ClH:1].[F:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)[CH:6]=[C:5]([OH:17])[C:4]=1[C:18]1[N:19]=[N:20][C:21]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:31])([CH3:32])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:22][CH:23]=1
Reactant: COc1cc(-c2cc(O)c(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(F)c2)ccn1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CN(c1ccc(-c2c(O)cc(-c3cc[nH]c(=O)c3)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Yield: 30.7 %

Procedure:
3-Fluoro-5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol hydrochloride salt (Example 40-1, 10 mg, 0.02 mmol) and pyridine hydrochloride (50 mg, 0.43 mmol) were heated at 170° C. for 15 minutes in a Biotage® Initiator microwave reactor. The reaction mixture was diluted with MeOH/DMSO, and purified via reverse phase preparative HPLC (10 to 45% acetonitrile in water, 0.1% trifluoroacetic acid as modifier). The appropriate fractions containing product were free based by catch and release using SiliaBond Propylsulphonic Acid® (4 eq, methanol as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and the resulting solid was suspended in CH3CN/H2O (3/1 mL). 1 M aqueous HCl (3 equivalents) was added and solvent was concentrated in vacuo to afford the title compound as a yellow solid (3 mg, 26%). LCMS Rt=0.47 min [Method Q]; [M+H]: 452.3; 1H NMR (400 MHz, MeOD) δ 8.28 (d, J=10.0 Hz, 1H), 8.07 (d, J=10.0 Hz, 1H), 7.69 (d, J=6.5 Hz, 1H), 7.25 (dd, J=11.0, 1.5 Hz, 1H), 7.19 (s, 1H), 6.89 (s, 1H), 6.85 (dd, J=6.5, 1.5 Hz, 1H), 5.07 (bs, 1H), 3.21 (s, 3H), 2.20-2.00 (m, 4H), 1.66 (s, 6H), 1.59 (s, 6H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:32](Cl)=[O:33].Cl>C(Cl)Cl.O>[F:27][C:28]([F:42])([F:43])[C:29]1[CH:30]=[C:31]([C:32]([NH:1][C@H:2]2[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[O:33])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H]1CC[C@H](N)[C@H]1c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a solution of 100 mg of amine from Example 62 in 5 mL of methylene chloride was added 0.2 mL of DIPEA and 175 mg of 3,5-bis(trifluoromethyl)benzoyl chloride. The reaction was stirred at room temperature for 1 h and was then poured into water and 2N HCl and extracted twice with methylene chloride. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 30 to 50% ethyl acetate in hexanes to obtain 100 mg of title compound. NMR (CDCl3): δ 1.8-1.9 (m, 1H), 2.05-2.2 (m, 1H), 2.2-2.4 (m, 2H), 3.08 (q, 1H), 3.42 (t, 1H), 3.67 (s, 3H), 4.65 (p, 1H), 6.80 (d, 1H), 6.99 (t, 2H), 7.22 (dd, 2H), 7.96 (s, 1H), 8.15 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]([OH:14])([P:10]([OH:13])([OH:12])=[O:11])[C:7]([OH:9])=[O:8])[CH3:3].[OH-].[Na+].[CH2:17]([Br:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C(O)C>[Br-:24].[C:7]([C:6]([OH:14])([P:10]([OH:13])([OH:12])=[O:11])[CH2:5][CH2:4][N+:2]([CH3:3])([CH3:1])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:9])=[O:8]
Reactant: BrCc1ccccc1
Reactant: CN(C)CCC(O)(C(=O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[N+](C)(CCC(O)(C(=O)O)P(=O)(O)O)Cc1ccccc1
Product: [Br-]

Procedure:
A solution of 2.27 g (0.01 mole) of 4-(N,N-dimethylamino)-2-hydroxy-2-phosphonobutanoic acid (prepared as described in Method 1) in 10 ml water and 40 ml ethanol is adjusted to pH 7.0 by addition of IN aqueous NaOH. To this is added 5.13 g (0.03 mole) of benzyl bromide, and the reaction is heated at about 50° for one day. The reaction is evaporated to dryness under reduced pressure. The resulting residue is slurried in water and the mixture is extracted several times with CHCl3. The aqueous solution is evaporated a little to get rid of traces of chloroform, and is treated with cation ion exchange resin in H+ form. The resin is filtered off, the aqueous solution is concentrated to a few ml, and ethanol is added dropwise to precipitate the product. This is purified by recrystallization from water/ethanol to give N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N,N-dimethyl-N-(phenylmethyl)ammonium bromide.
Reaction SMILES: C(C#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14]Br.O.[C:17]([O:20]CC)(=[O:19])[CH3:18]>[H-].[Na+].O1CCCC1>[C:2]1([C:18]2([C:17]([OH:20])=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1ccccc1
Reactant: BrCCCCBr
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a stream of argon, 60% sodium hydride was dissolved in 10 ml of tetrahydrofuran, and the solution was mixed with 2.0 g of benzyl cyanide, stirred for 1 hour at room temperature, further mixed with 3.69 g of 1,4-dibromobutane and again stirred for 16 hours at room temperature. The reaction mixture was mixed with water and ethyl acetate, and the resulting organic layer was separated, washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was subjected to silica gel column chromatography, and the resulting hexane eluate was mixed with 45 ml of sulfuric acid and subjected to 24 hours of heating under reflux. After cooling down to room temperature, the reaction solution was mixed with ice water and ethyl acetate to separate water layer which was subsequently mixed with concentrated hydrochloric acid and ethyl acetate, and the resulting organic layer was separated, washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. By removing the solvent by distillation under a reduced pressure, 978 mg of 1-phenylcyclopentanecarboxylic acid was obtained.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[N:22]=1>>[CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[N:22]=3)[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)n1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1ccccc1)CO2
Product: O[C@@H]1c2cc(OCc3cccc(Cl)n3)ccc2OC[C@H]1Cc1ccccc1

Procedure:
By the method of Example 5, 0.50 g (1.96 mmol) of trans-3-benzyl-4,6-chromandiol and 445 mg (2.16 mmol) of 2-chloro-6-(bromomethyl)pyridine were converted to present title product purified by recrystallization from CH2Cl2 /hexane, to yield 0.50 g (67%) of present title compound, m.p. 117-119° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([O:22][CH3:23])[CH:11]=2)=[O:8])[NH:5][CH:6]=1.Br[CH2:25][CH2:26]Br.[OH-].[Na+]>ClC(Cl)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:26][CH2:25][N:5]2[CH:6]=1
Reactant: BrCCBr
Reactant: COc1cc(NC(=O)c2cc(Br)c[nH]2)ccc1OCC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc(N2CCn3cc(Br)cc3C2=O)ccc1OCC(C)(C)O
Temperature: 50 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
A mixture of 4-bromo-N-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide (1.50 g, 3.92 mmol), 1,2-dibromoethane (1.68 mL, 19.6 mmol), NBu4Br (1.26 g, 3.93 mmol) and 1N NaOH (19.6 mL, 19.6 mmol) in dichloroethane (19.6 mL) was allowed to stir at 50° C. for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (150 mL), washed with water, brine, dried over anhydrous Na2SO4 and concentrated. To the resulting brown oil was triturated with EtOAc (25 mL) to give 643 mg of the title compound as a light gray solid: 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 6H), 2.67 (br. s., 1H), 3.83 (s, 2H), 3.85 (s, 3H), 4.04-4.08 (m, 2H), 4.22-4.26 (m, 2H), 6.78 (t, J=5.5 Hz, 2H), 6.90-6.95 (m, 2H), 6.99 (s, 1H); HPLC a) column: Phenomenex Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 2.730 min retention time, (99%); HPLC b) column: Phenomenex Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.748 min retention time; MS (ES) 409 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4](NCC)=[O:5].[C:17](=[O:28])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])OC(C)(C)C.[C:29](#[N:31])[CH3:30]>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:14])([CH3:15])[CH3:16])[C:3]=1[C:4]([CH2:30][CH2:29][NH:31][C:17](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:5]
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Product: CC(C)(C)OC(=O)NCCC(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound of example 45 (3.83 g, 15 mmol) and di-t-butyl carbonate (3.60 g, 16.5 mmol) in acetonitrile was added 4-dimethylaminopyridine (0.18 g, 1.5 mmol). The solution was stirred at RT for 1 day, additional di-t-butyl carbonate (3.60 g) was added and stirring was continued for 3 days. Additional di-t-butyl carbonate (3.60 g) was added and the reaction was stirred overnight and concentrated. The residue was diluted with ether, washed with sat citric acid, sat NaHCO3, brine, dried (MgSO4) and concentrated to afford the title compound. The crude product was purified by flash chromatography (ethyl acetate /hexanes) and recrystallization from hexanes (-78° C.) to afford the title compound as a white solid (2.65 g, 50%). m.p. 51°-52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](OC)=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].[NH2:32][C:33]1([C:39]([OH:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:32][C:33]3([C:39]([OH:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]
Reactant: NC1(C(=O)O)CCCCC1
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Product: Cc1ccccc1-c1ccc(C(=O)NC2(C(=O)O)CCCCC2)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Product: Cl
Yield: 106.2 %

Procedure:
According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 465 mg (1.06 mmol) of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylate (example 4.7) and 174 mg (1.22 mmol) of 2-aminocyclohexane-2-carboxylic acid, we obtain 330 mg of 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride in the form of white powder.
Reaction SMILES: [N:1]1([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14](F)(=[O:16])=[O:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH3:18]>C1COCC1>[N:1]1([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:18])(=[O:16])=[O:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(F)c1ccccc1S(=O)(=O)N1CCC1
Reactant: N
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1S(=O)(=O)N1CCC1

Procedure:
In a 1-l flask was placed 9.8 g. of 2-(azetidin-1-ylsulfonyl)benzenesulfonyl fluoride and 500 ml of THF. Then 9 ml of ammonia was added and the mixture was refluxed for two days. Four 25 ml portions of liquid ammonia were then added to the refluxing solution over a 48 hour period. The reaction mixture was concentrated and the residue chromatographed on silica gel (dichloroethane). The desired product was collected to give 4.9 g of a solid m.p. 121°-123° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>[Fe].CCOCC>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([C:11]#[N:12])=[N:4][CH:5]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1Br
Agent: [Fe]
Solvent: CCOCC
Product: N#Cc1ncc(N)cc1Br

Procedure:
3-Bromo-2-cyano-5-nitropyridine (0.4g, 1.75 mmol) and iron powder (0.51g, 8.8 mmol, 325 Mesh) were reacted as described in example 762D. The crude solid obtained by trituration with ether was purified by SiO2 Prep-TLC using 4:1 CH2Cl2/ether as eluent to give compound 769A (0.16 g, (65%) as an off-white solid. HPLC: 100% at 1.77 min(YMC S5 ODS column) eluting with 10–90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 197.93 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl[CH2:15][C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:13][O:12][C:10]([C:5]1[C:4]2[CH:3]=[CH:2][N:1]([CH2:15][C:16](=[O:17])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:11]
Reactant: CCN(CC)C(=O)CCl
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)Cn1ccc2c(C(=O)OC)cccc21

Procedure:
Methyl indole-4-carboxylate (50 mg, 2.85 mmol) and 2-chloro-N,N-diethylacetamide (854 mg, 5.71 mmol) are dissolved in DMF (10 ml) and to the solution is added potassium carbonate (986 mg, 7.14 mmol). The reaction is heated using microwave radiation at 100° C. for 2 hours, then diluted with DCM (60 ml) and washed with water (5×10 ml). Drying over MgSO4, concentration in vacuo, and trituration with Et2O affords 1-Diethylcarbamoylmethyl-1H-indole-4-carboxylic acid methyl ester; [M+H]+ 289.