Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][N:16]([C:18]1[CH:28]=[CH:27][C:21]([CH:22]=[CH:23][C:24](O)=O)=[CH:20][CH:19]=1)[CH3:17]>>[CH3:15][N:16]([C:18]1[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[CH:20][CH:19]=1)[CH3:17]
Reactant: CN(C)c1ccc(C=CC(=O)O)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(N(C)C)cc3)nc2n(CC)c1=O
Yield: 52.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.30 g (17.3 mmol) of 4-(N,N-dimethylamino)cinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 2.78 g (yield 52%) of Compound 162 as yellow needles.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][C:16]=2[F:25])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.CO>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]2[N:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:16]=2[F:25])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(F)c(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2nc(C(=O)O)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of methyl 6-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-5-fluoropicolinate (1.0 equiv.) in THF/MeOH (2:1, 0.09 M) was added LiOH (1.5 equiv.). The reaction mixture was stirred overnight at room temperature, then 1N HCl and ethyl acetate were added, the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 6-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-5-fluoropicolinic acid as a mixture of isomers (3:1) in 82% yield. LC/MS=354.2 (M+H), Rt=1.38 and 1.41 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:29][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ncc(C#N)cc2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: N#Cc1cnc(-c2ccc(CBr)cc2)c(-c2ccccc2)c1

Procedure:
To a mixture of 6-(4-methylphenyl)-5-phenylnicotinonitrile (0.250 g, 0.925 mmol) in CDCl3 (6 mL) was added NBS (0.173 g, 0.971 mmol) and benzoyl peroxide (0.045 g, 0.185 mmol). The reaction was heated to reflux for 15 hr. The reaction mixture was then cooled and concentrated to give crude 6-[4-(bromomethyl)phenyl]-5-phenylnicotinonitrile. LRMS m/z (M+H) calcd: 348.9, found: 348.9.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=2)[C:42]#[N:43])O1>>[C:42]([C:41]1[CH:44]=[C:37]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:18])([F:19])[F:20])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:38]=[N:39][CH:40]=1)#[N:43]
Reactant: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(SC(F)(F)F)c(F)c3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 205.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.10 min, m/z=504.3 [M+H]+, m/z=502.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.83 (dd, J=8.72, 4.33 Hz, 1H) 2.84 (d, J=11.29 Hz, 1H) 3.13-3.25 (m, 2H) 3.34-3.41 (m, 1H) 4.14-4.24 (m, 1H) 4.87 (d, J=3.51 Hz, 1H) 7.65 (dd, J=8.91, 1.88 Hz, 1H) 7.74 (t, J=8.16 Hz, 1H) 7.95 (dd, J=11.80, 2.13 Hz, 1H) 8.07 (d, J=2.38 Hz, 1H) 8.38 (t, J=2.07 Hz, 1H) 8.78 (d, J=2.26 Hz, 1H) 8.88 (d, J=2.13 Hz, 1H) 9.01 (d, J=2.01 Hz, 1H) 10.43 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][N:5]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)[C:6]#[N:7].[OH-:15].[Na+]>Cl>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][N:5]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)[C:6]([NH2:7])=[O:15]
Reactant: [OH-]
Reactant: CN(C)CCN(C#N)c1cnccn1
Agent: Cl
Agent: [Na+]
Product: CN(C)CCN(C(N)=O)c1cnccn1
Reaction time: 1 h

Procedure:
N-(2-Dimethylaminoethyl)-N-(2-pyrazinyl) cyanamide (2.83 g, 0.015 mole) is dissolved in 20 ml of 6 N hydrochloric acid. After one hour, the mixture is made alkaline with concentrated sodium hydroxide and concentrated. The residue is extracted with ether which is concentrated. The residue is crystallized from butyl chloride and N-(2-dimethylaminoethyl)-N-(2-pyrazinyl)urea melting at 105°-108° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH3:11].C(N(CC)C(C)C)(C)C>C(O)CCC>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:7]2[C:2]([Cl:1])=[C:3]([NH2:9])[N:4]=[CH:5][N:6]=2)=[CH:19][CH:20]=1)[CH3:11]
Reactant: Nc1ncnc(Cl)c1Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc(Nc2ncnc(N)c2Cl)cc1
Temperature: 115 °C
Yield: 65.3 %

Procedure:
To a vial with stirbar were added 5,6-dichloro-pyrimidin-4-ylamine (1.4 g, 8.537 mmol, 1.0 eq), (4-amino-phenyl)-acetic acid ethyl ester (4.3 g, 23.993 mmol, 2.8 eq), N,N-diisopropylethylamine (4.5 ml, 25.611 mmol, 3.0 eq), dissolved in n-butanol (100 ml). The reaction suspension was flushed with nitrogen and heated to 115° C. for 8 days. The mixture was concentrated in vacuo, dissolved in EtOAc, washed with water (2×) and brine (1×), dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified using Biotage column chromatography eluting from 30-70 EtOAc/hexanes. Fractions containing the desired product were combined and concentrated under reduced pressure to afford (4-(6-amino-5-chloro-pyrimidin-4-ylamino)-phenyl)-acetic acid ethyl ester (1.71 g, 49% yield) as white crystals. MS: m/z=307 [M+H]+. 1H-NMR (DMSO-d6) δ 8.41 (s, 1H), 7.93 (s, 1H), 7.55 (d, 2H), 7.19 (d, 2H), 6.76 (bs, 2H), 4.11 (q, 2H), 1.21 (t, 3H).
Reaction SMILES: [OH:1][CH:2](/[CH:12]=[CH:13]/[C:14]1[C:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][N:17]2[C:26]=1[CH:27]([CH3:29])[CH3:28])[CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)C.[Pd]>[OH:1][CH:2]([CH2:12][CH2:13][C:14]1[C:15]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][N:17]2[C:26]=1[CH:27]([CH3:28])[CH3:29])[CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(=O)CC(O)CCc1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Yield: 103.8 %

Procedure:
A solution of ethyl (E)-5-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)-3-oxohept-6-enoate (0.94 g; prepared as described in Reference Example 2) in ethanol (42 ml) was reduced catalytically under a hydrogen atmosphere using 5% w/w palladium on charcoal (0.254 g) and 5% w/w palladium on calcium carbonate (0.226 g) as catalysts. The mixture was filtered to remove the catalysts and the filtrate was evaporated, to give ethyl 5-hydroxy-7-(3-isopropyl1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)-3-oxoheptanoate (0.98 g) in the form of a pale green gum.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:37]=[CH:36][C:14]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26]C)=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]=3[C:28]3[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]=3[C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)=[CH:36][CH:37]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 8 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of 1-[4-[2-(1-piperdinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)-6-methoxynaphthalene hydrochloride (1.00 g, 1.92 mmol) in 20 mL of anhydrous methylene chloride under N2 at 0° C. was added boron tribromide (0.74 mL, 7.71 mmol). The resulting mixture was allowed to warm to 8° C. and stirred for 2 hours. The reaction was then poured into a stirring solution of cold saturated sodium bicarbonate (200 mL). When gas evolution ceased, the aqueous layer was extracted with 5% methanol/chloroform (3×100 mL). The organic layer was combined, dried (sodium sulfate), and concentrated in vacuo to an oil. The crude free base was dissolved in 20 mL of ethyl acetate, and treated with ethyl ether-hydrochloric acid. A precipitate formed that was collected by filtration. Drying in vacuo provided 798 mg (83%) of 1-[4-[2-(1-piperdinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)-6-hydroxynaphthalene hydrochloride as a white solid. mp 130-136° C. 1H NMR (DMSO-d6) δ 9.89 (s, 1H), 9.80 (bs, 1H), 9.46 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.64 (d, J=9.2 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.20 (d, J=2.2 Hz, 1H), 7.04 (dd, J=9.2, 2.2 Hz, 1H), 6.82 (d, J=9.1 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 6.61 (d, J=9.1 Hz, 2H), 4.21 (m, 2H), 3.45-3.33 (m, 4H), 2.92 (m, 2H), 1.80-1.63 (m, 5H), 1.35 (m, 1H). FD mass spec: 456. Anal. Calcd. for C29H29NO4 ·1.0 HCl: C, 70.80; H, 6.15; N, 2.85. Found: C, 70.52; H, 6.19; N, 2.55.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].[CH2:29](I)[CH3:30]>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:29][CH3:30])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 0.5 g of approximately 55 % sodium hydride, and the solution was stirred for 30 minutes. To this was further added 4.7 g of ethyl iodide and stirring was further continued for 1.5 hours at room temperature. After the reaction was complete, the solvent was distilled off from the mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product, which was then recrystallized from methanol to give 2.7 g of 1-(m-nitrophenyl)-3-ethylquinazoline-2,4 (1H, 3H)-dione as light brown prisms, melting at 193°-194° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[F:8][C:9]1[CH:10]=[C:11]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH:12]=[CH:13][CH:14]=1.C(N(CCCC)CCCC)CCC>[OH-].[Na+].O>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[C:21]([OH:22])=[N:1][C:2]3[N:3]([N:4]=[C:5]([CH3:7])[N:6]=3)[C:16]=2[OH:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(F)c1
Reactant: Cc1nc(N)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Cc1nc2nc(O)c(-c3cccc(F)c3)c(O)n2n1
Yield: 88.7 %

Procedure:
5 g (51.87 mmol) 3-Amino-5-methyl-1,2,4-triazole, 16.2 g (67.4 mmol) diethyl (3-fluorophenyl)malonate and 20.4 mL tributylamine are stirred at 180° C. over night. The mixture is diluted with 2N NaOH solution and water and extracted three times with methyl-tert. butylether. These organic extracts are discarded. The aqueous phase is acidified at 0° C. with concentrated HCl until pH 3. The white precipitate is collected by filtration, washed with water (4 L) and dried in vacuo at 50° C. 11.97 g (88.7%) of the product are obtained and are used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([OH:13])=O)[C:6](=[O:9])[C:7]=1[Br:8].C(Cl)(=O)C(Cl)=O.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([NH:27][CH2:26][C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)=[O:13])[C:6](=[O:9])[C:7]=1[Br:8]
Reactant: NCc1ccncc1
Reactant: O=C(O)Cn1ncc(Br)c(Br)c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cn1ncc(Br)c(Br)c1=O)NCc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
2-(4,5-Dibromo-6-oxopyridazin-1(6H)-yl)acetic acid (1.48 g, 4.38 mmol) in tetrahydrofuran (30 mL) was mixed with N,N-dimethylformamide (1 drop) and oxalyl chloride (570 μL, 6.53 mmol) at room temperature and stirred at room temperature for 30 minutes. The solvent was removed by distillation, and the residue was dissolved in tetrahydrofuran (10 mL) and added dropwise to 4-picolylamine (538 μL, 5.22 mmol) and triethylamine (1.22 mL, 8.70 mmol) in tetrahydrofuran (20 mL) and stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was mixed with water and extracted with chloroform three times, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting solid was washed with 2-propanol-hexane to give the desired product (572 mg, 33% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7](O)=[N:8][C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:20].CO>CC#N.[N+](C)(C)(C)C.[Cl-]>[Cl:20][C:7]1[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:11][N:10]=[C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:8]=1
Reactant: CS(=O)(=O)Cc1ncc(OCC2CC2)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CO
Solvent: CC#N
Product: CS(=O)(=O)Cc1ncc(OCC2CC2)c(Cl)n1
Temperature: 80 °C
Yield: 49.1 %

Procedure:
To the title compound of step 1 (1.9 g, 7.36 mmol) in MeCN (30 mL) was added Me4NCl (1.6 g, 14.72 mmol) and POCl3 (6.8 g, 44.16 mmol). The mixture was heated at 80° C. for 6 h. After concentration under vacuum, the residue was subjected to EA extractive work up. Trituration with methanol (20 mL) gave the title compound (1 g, yield: 49.3%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 5.50 (s, 2H), 3.85 (d, J=6.8 Hz, 2H), 3.09 (s, 3H), 1.31-1.28 (m, 1H), 0.70-0.65 (m, 2H), 0.39-0.36 (m, 2H). LCMS: 277.1 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]1[C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:42]([C:39]1[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][C:38]=1[O:46][C:47]([F:48])([F:49])[F:50])(=[O:44])=[O:43])[C:6](=[O:11])[C:5]2([N:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]1[C:29]([N:31]([CH3:32])[CH3:33])=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(N2Cc3ccccc3C2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3Cc4ccccc4C3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 1.00 g of 2-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl isoindoline-1-carboxamide (diastereoisomer mixture), which is the compound described in Preparation 3.5 of the brochure Publication No. WO01/64668, and 692 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 770 mg (Isomer mixture A, colorless amorphous) and 423 mg (Isomer mixture B, colorless amorphous) each of mixtures of diastereoisomers of the title compound were obtained by a similar method to Example 2.
Reaction SMILES: [C:1]([NH:9][C@H](C(O)=O)CCC(O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[CH:24]=CC=C[CH:20]=1>>[C@H:1]1([NH2:9])[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:19][CH2:20]1
Reactant: O=C(O)CC[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: c1ccccc1
Product: N[C@@H]1CCCc2ccccc21

Procedure:
The (R) amine is made in the same way as described in Example 8, but from the salt from N-benzoyl-(S)-glutamic acid. It has [α]D25 -54.0° (c 5.1, benzene).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[CH2:18][C:19]([OH:21])=O.[N:22]1([CH2:28][C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C@H:37]([NH2:41])[CH2:36][CH2:35][CH2:34]3)=[CH2:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[CH2:18][C:19]([NH:41][C@H:37]1[C:38]2[C:33](=[CH:32][C:31]([C:29]([CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH2:30])=[CH:40][CH:39]=2)[CH2:34][CH2:35][CH2:36]1)=[O:21]
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)C2CC(=O)O)cc1
Reactant: C=C(CN1CCCCC1)c1ccc2c(c1)CCC[C@H]2N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: C=C(CN1CCCCC1)c1ccc2c(c1)CCC[C@H]2NC(=O)CC1C(=O)NCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
To a 20 mL flask equipped with stirring was added [3-oxo-1-(toluene-4-sulfonyl)-piperazin-2-yl]-acetic acid (104 mg, 0.33 mmol), 6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-ylamine (Step g, 90 mg, 0.33 mmol), EDC (Aldrich, 96 mg, 0.50 mmol), HOBt (Aldrich, 45 mg, 0.33 mmol), and CH2Cl2 (2 mL). The reaction mixture was stirred at RT overnight and diluted with CH2Cl2 (50 mL). The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by preparative TLC in 10% MeOH-CH2Cl2 to afford the title compound as a mixture of two diastereomers. MS (ESI): 565 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O.Cl>O1CCOCC1>[CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:33])[F:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 51.3 %

Procedure:
To a solution of ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (71.2 g, 147 mmol) in 1,4-dioxane (400 mL) an aqueous solution of LiOH.H2O (220 mL, 2 M, 3 eq) was added. The resulting two phase mixture was stirred at 50° C. under N2 for 5 h. The reaction mixture was allowed to cool and the pH adjusted to 3-4 with 6 N HCl. The solvent was rotary evaporated and to the two phase aqueous/product mixture CH2Cl2 added. The layers were separated and the organics washed with H2O (2×300 mL). The combined aqueous phases were re-extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered and rotary evaporated. The dark brown oily residue was taken up in MeOH and the solvent evaporated under reduced pressure. The dark brown residue was taken up again in a minimum amount of MeOH and left in the fridge over 16 h. The precipitate was collected under suction, washing the solids with hexanes, and dried under high vacuum to afford the product (34.5 g, 51%) as an off-white solid. The filtrate containing product was concentrated to dryness to give a dark brown fluffy solid (33.6 g) which was processed further separately. LCMS m/z=458.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.76-1.57 (m, 4H), 1.93-1.81 (m, 2H), 2.16-1.97 (m, 3H), 2.38 (dd, J=15.2, 8.8 Hz, 1H), 2.80-2.62 (m, 4H), 3.32-3.23 (m, 1 H), 3.54-3.44 (m, 1H), 5.15 (s, 2H), 6.74 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.76-7.70 (m, 2H), 10.48 (s, 1H), 12.20 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[C:11](=O)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[C:11](=[S:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1c(-c2cccc(I)c2)noc1=O
Solvent: Cc1ccccc1
Product: Cn1c(-c2cccc(I)c2)noc1=S
Yield: 95.5 %

Procedure:
3-(3-Iodophenyl)-4-methyl-1,2,4-oxadiazol-5(4H)-one (400 mg, 1.32 mmol) obtained in Step 2 was dissolved in toluene (10 mL), and the mixture was heated to reflux for 7 days after adding Lawesson's reagent (801 mg, 1.98 mmol). The mixture was then purified by silica gel column chromatography to give 3-(3-iodophenyl)-4-methyl-1,2,4-oxadiazole-5(4H)-thione (401 mg, 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:26])[C@H:16]([CH3:25])[NH:17]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:26])[C@H:16]([CH3:25])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)NCCNC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
A solution of 12.0 g (0.033 mol) of (1g) in 25 ml of dichloromethane was cooled with an ice bath and 25 ml of trifluoroacetic acid was added. The solution was stirred at ca 5° C. for 20 minutes, then allowed to stir to room temperature. After 90 minutes, the dichloromethane and trifluoroacetic acid were removed in vacuo. The resulting residue was dissolved in 200 ml of ethyl acetate and washed with 2M sodium hydroxide (200 ml) and brine (100 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to produce 7.86 g (90% yield) of L-alanine, 2-(benzyloxycarbonylamino)ethyl amide (1h) as a white solid. 1H NMR (CDCl3) δ 1.28(d, 3H), 2.09(m, 2H), 3.33(m, 4H), 3.47(q, 1H), 5.07(s, 2H), 5.59(bt, 1H), 7.33(bs, 5H), 7.69(bt, 1H); 13C NMR (CDCl3) δ 21.3, 39.5, 40.9, 50.4, 66.6, 128.0, 128.1, 128.4, 136.4, 156.9, 176.7.