Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:21]([CH3:22])[CH2:20][CH2:19][C@@:16]4([C:17]=2[CH:18]=1)[C@H:11]3[CH2:12][CH2:13][O:14][CH2:15]4)(=[O:3])[CH3:2].C(=O)([O-])[O-:24].[K+].[K+].[C:29]1([O:35]C(Cl)=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:21]([C:22]([O:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:24])[CH2:20][CH2:19][C@@:16]4([C:17]=2[CH:18]=1)[C@H:11]3[CH2:12][CH2:13][O:14][CH2:15]4)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@@H]1CCOC3
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)Oc1ccccc1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc2c(c1)[C@]13CCN(C(=O)Oc4ccccc4)[C@H](C2)[C@@H]1CCOC3

Procedure:
A mixture of XXVI (0.01 m) from Step (a) above, 4 g potassium carbonate and phenylchloroformate (0.03 m) in 50 ml toluene is heated at reflux for 24 hours. The cooled reaction mixture is treated with water. The toluene layer is separated, dried (MgSO4), filtered and concentrated to give the title product as a crude oil used directly in the next reaction.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][C:8]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)([OH:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=1)(C)(C)C.[OH-].[Li+]>CO.O>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][C:8]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)([OH:25])[CH2:7][C:6]([OH:31])=[O:5])[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)CC(O)(CCc1cccc(OCc2ccccc2)c1)C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC(O)(CCc1cccc(OCc2ccccc2)c1)C1CCCC1

Procedure:
The title compound was prepared by dissolving (S) 5-(3-benzyloxy-phenyl)-3-cyclopentyl-3-hydroxy-pentanoic acid tert-butyl ester (1.6 g, 3.8 mmol) from Example CCCCC in methanol (20 mL). Lithium hydroxide (0.32 g, 7.6 mmol) in H2O (5 mL) was added and the reaction heated to reflux overnight, cooled and pumped to dryness under vacuum. The product was partitioned between H2O and Et2O. The aqueous layer was decanted, acidified with 1N HCl and extracted with EtOAc. The organic phase was dried (MgSO4), and concentrated to give the title compound. 1H-NMR (CDCl3) δ 1.3-1.7 (m, 8 H), 1.85-1.95 (m, 2 H), 2.3 (t, 1 H), 2.45-2.7 (m, 4 H), 5.1 (s, 2 H), 6.75-6.85 (m, 3 H), 7.15 (t, 1 H), 7.3-7.45 (m, 5 H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1
Reactant: COC(=O)Cl
Reactant: CCCN1C(=O)Cc2cc(N3C[C@@H](CN)OC3=O)cc(F)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC)OC3=O)cc(F)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.038 ml, 0.480 mmol) is added dropwise to (R)-5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-7-fluoro-1-propyl-1,3-dihydro-indol-2-one (0.135 g, 0.320 mmol) and diisopropylethylamine (0.235 ml, 1.28 mmol) in dichloromethane (3 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% MeOH/DCM) to give the title compound as an off white solid. HPLC r.t. 4.40 min; 1H NMR (300 MHz, CDCl3) 7.30 (m, 1H), 7.21 (m, 1H), 5.10 (t, 1H), 4.77 (m, 1H), 4.02 (t, J=9 Hz, 1H), 3.77-3.82 (m, 3H), 3.68 (s, 3H), 3.57 (s, 2H), 3.49-3.63 (m, 2H), 1.69 (m, 2H), 0.95 (t, J=7.5 Hz, 3H); MS for C17H20F2N3O5 m/z 366.1 (M+H)+.
Reaction SMILES: C(O)(=O)[C@@H](C1C=CC=CC=1)O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH:17]([NH2:19])[CH3:18]>C(O)(C)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C@H:17]([NH2:19])[CH3:18]
Reactant: COc1cccc(C(C)N)c1
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CC(C)O
Product: COc1cccc([C@@H](C)N)c1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of 14.0 g (92.0 mmol) of (R)-(-)-mandelic acid (Aldrich, 99+%), 14.0 g (92.7 mmol) of (±) 3-methoxy-α-methylbenzylamine and 500 mL of isopropanol was brought to reflux and gravity filtered while hot. The solution was then seeded at 50° C. with diastereomerically-pure seeds. After cooling to room temperature, the mixture was filtered to afford 10.9 g of a fluffy, white solid. This was recrystallized from 500 mL of isopropanol. The solids were collected then partitioned between ethyl acetate and saturated Na2CO3. The organics were washed with saturated NaCl, dried with Na2SO4, and concentrated to afford 5.8 g (83%) of a yellow oil. NMR analysis of the derived camphorsulfonamide (FIG. 6) indicated that the chemical is enantiomerically pure, to the limits of detection of NMR. This oil was distilled, b.p. 118°-120° C. at aspirator pressure, α!D =3.8° (c+1 in 2N HCl). Preliminary results suggest that this compound may form a carbonate upon exposure to air. It is therefore recommended that the chemical be stored under an inert atmosphere.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Br:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[BrH:11].[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1
Reactant: Cc1cc2cccnc2[nH]1
Reactant: BrCCc1ccccc1
Solvent: CC#N
Product: Br
Product: Cc1cc2cccn(CCc3ccccc3)c-2n1
Yield: 92.6 %

Procedure:
A solution of 85 mg (0.64 mmol) of 2-methyl-pyrrolo[2,3-b]pyridine and 140 mg(0.76 mmol) of (2-bromoethyl)benzene in 1 ml acetonitrile was refluxed for 40 h. The solvent was evaporated and the residue was treated with ether. The solid that formed was isolated by filtration to give 188 mg (62%) of 2-methyl-7- (2-phenylethyl)pyrrolo[2,3-b]pyridinehydrobromide.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][N:8]=[C:9]=[S:10])=[O:5].[CH3:11][C:12]([CH3:32])=[CH:13][CH2:14][CH2:15]/[C:16](/[CH3:31])=[CH:17]/[CH2:18][CH2:19]/[C:20](/[CH3:30])=[CH:21]/[CH2:22][S:23][CH2:24][C@H:25]([NH2:29])[C:26]([OH:28])=[O:27].C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[CH2:2]([O:3][C:4](=[O:5])[CH2:6][CH2:7][NH:8][C:9](=[S:10])[NH:29][C@@H:25]([CH2:24][S:23][CH2:22]/[CH:21]=[C:20](\[CH3:30])/[CH2:19][CH2:18]/[CH:17]=[C:16](\[CH3:31])/[CH2:15][CH2:14][CH:13]=[C:12]([CH3:32])[CH3:11])[C:26]([OH:28])=[O:27])[CH3:1]
Reactant: CCOC(=O)CCN=C=S
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=S)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 mL round bottom flask, to a suspension of ethyl-3-isothiocynato propionate (159 mg, 1 mmol) and S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) in THF (5 mL) was added N,N-diisopropyl-ethyl-amine (0.87 mL, 5 mmol) dropwise. The solution was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (60 mL) and washed by 0.5 N HCl (10 mL×1), H2O (10 mL×1) and brine (10 mL×1). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (220 mg, 45%) to yield Compound N-73. 1H-NMR (500 MHz, CD3OD): δ 1.17 (t, J=5.0 Hz, 3H), 1.50 (s, 3H), 1.51 (s, 3H), 1.57 (s, 3H), 1.59 (s, 3H), 1.86-2.06 (m, 8H), 2.54 (t, J=5.0 Hz, 2H), 2.77 (dd, J=5.0, 15.0 Hz, 1H), 2.95-2.96 (m, 1H), 3.05-3.06 (m, 1H), 3.16-3.20 (m, 1H), 3.68 (broad, 2H), 4.06 (q, J=5.0 Hz, 2H), 5.00-5.01 (m, 2H), 5.09-5.14 (m, 2H). 13C-NMR (125 MHz, CD3OD): δ 14.65, 16.19, 16.31, 17.83, 25.97, 27.39, 27.80, 30.70, 33.22, 33.91, 34.80, 40.80, 40.90, 57.89, 61.03, 61.71, 61.93, 121.35, 121.70, 125.16, 132.11, 136.24, 140.52, 173.76, 174.47, 210.16; ES-MS: mass calcd for Chemical Formula: C24H40N2O4S2 484.72. Found (M+) m/z 485.3, (M+Na) m/z 507.3.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[SH:18].C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C=O)C>O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][S:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Cl:1])[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: Fc1ccccc1-c1noc2c(Cl)c(S)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc2c(-c3ccccc3F)noc2c1Cl
Temperature: 50 °C

Procedure:
3.2 g of 7-chloro-3-(2-fluorophenyl)-6-mercapto-1,2-benzisoxazole, 3.1 g K2CO3 and 3.67 g of ethyl bromoacetate are added to 60 ml DMF and warmed for two hours at 50° C. with stirring. The solution is poured into 700 ml H2O and extracted with ethyl acetate. The combined organic extracts are dried over K2CO3, and the solvent is removed in vacuo to afford ethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]thio}-acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2Cl.CN1C(=O)CCC1.[N-:27]=[N+:28]=[N-:29].[Na+].O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2[N:27]=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cccc(-c2cc(Cl)c3cc(Br)ccc3n2)c1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Temperature: 60 °C

Procedure:
Into a 250 mL three-neck round-bottom flask equipped with a condenser, magnetic stirrer, silicone oil heating bath, nitrogen inlet and gas outlet was placed 3.2 g (9.50 mmoles) of 6-bromo-4-chloro-2-(3-fluorophenyl)-quinoline. To this was added 75 mL of N-methyl pyrrolidinone then 6.0 g (95 mmoles, 10 equiv.) of sodium azide. The stirring mixture was then warmed to 60° C. for 18 hr. At the end of this time the reaction was cooled, then poured into a 1 L separatory funnel containing 500 mL water and 250 mL of ethyl acetate. The pH was adjusted to 9.0 the layers were separated. The aqueous layer was then extracted twice with 100 mL of ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and concentrated to give a product, which was carried to the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[NH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O-:50])=[O:49].[Na+]>>[CH3:39][O:38][N:33]1[C:34]([CH3:37])([CH3:36])[CH2:35][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]3[CH2:14][C:15]([CH3:23])([CH3:24])[N:16]([O:21][CH3:22])[C:17]([CH3:20])([CH3:19])[CH2:18]3)[N:7]=[C:2]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[N:3]=2)[CH2:31][C:32]1([CH3:40])[CH3:41]
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCCCCC(=O)[O-]
Agent: [Na+]
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCCCCC(=O)O)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from 2-chloro-4,6-bis[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and sodium 6-aminohexanoate according to the procedure of Example 15.
Reaction SMILES: B(F)(F)F.CCOCC.[Li+].[C-:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[C:21]2([CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:20]1>C1COCC1>[OH:19][C:21]1([CH2:20][C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: [C-]#Cc1ccccc1
Agent: FB(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(CC#Cc2ccccc2)CC1
Temperature: -75 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Boron trifluoride diethyl etherate (0.131 mL, 1.03 mmol) followed by lithium phenylacetylide (1M in THF, 1.03 mL, 1.03 mmol) was dropped into a solution of Compound 256a (200 mg, 0.938 mmol) in THF (5 mL) stirred at −75° C. under nitrogen atmosphere. Stirring and cooling were kept on for 2 h and after overnight stirring at r.t., the reaction mixture was quenched with water and EtOAc. The combined extracts were washed, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (EtOAc—Petroleum Ether 85:15) affording the title product (272 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[Ca+2].Br.[Br:19][CH2:20][CH2:21][NH:22]C1C=CC=CC=1>O>[OH2:11].[BrH:19].[CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH:4][CH2:20][CH2:21][NH2:22]
Reactant: BrCCNc1ccccc1
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: Cc1cc(N)c([N+](=O)[O-])cc1NCCN
Temperature: 0 °C

Procedure:
A suspension of 0.05 mol (8.35 g) of 2-methyl-4-amino-5-nitroaniline and 0.035 mol (3.5 g) of calcium carbonate in 100 ml of water are first heated on a boiling waterbath, while stirring. 0.07 mol (14.35 g) of β-bromoethylaniline hydrobromide dissolved in 20 ml of water is added a little at a time, while stirring. After the reaction mixture had been heated on a boiling waterbath for 2 hours, it is filtered hot. After the filtrate has been cooled at 0° C. for 24 hours, the expected product, which has crystallised in the form of the hydrobromide, is filtered off with suction. The crude product is washed with acetone and then recrystallised from boiling water. After filtering off with suction, washing with acetone and drying in vacuo, 2-methyl-4-amino-5-nitro-N-β-aminoethylaniline hydrobromide monohydrate is obtained.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[Cl:22][C:23]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[CH:28][CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:23]=2[Cl:22])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Reactant: N#Cc1cccc([N+](=O)[O-])c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2ccccc2Cl)nc1-c1cccc([N+](=O)[O-])c1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (1.72 g), 2-chloro-3-nitrobenzonitrile (1.00 g), anhydrous aluminum chloride (0.70 g) and o-dichlorobenzene (20 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.12 g of desired compound (melting point: 124.0°-125.0° C.).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[NH:9][C:8]2=O)(=[O:3])[CH3:2].CN(C=O)C.O=S(Cl)[Cl:37]>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[Cl:37])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)[nH]c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Cl)c2cc1OC(C)=O
Temperature: 25 °C

Procedure:
To a mixture of 2-[(3-phenyl)phenyl]-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (3.6 g, 9.32 mmole) in SOCl2 (40 mL) was added DMF (1 mL) and the reaction was stirred at reflux for 16 h. The mixture was cooled to RT and then the volatiles were removed in vacuo. The crude product was dissolved in CHCl3 (300 mL) and washed with saturated NaHCO3 solution (3×150 mL), water (2×150 mL) and brine (1×150 mL) and dried with Na2SO4. The solution was concentrated in vacuo to yield 4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin-6-yl acetate (4.0 g, 9.88 mmole). HPLC retention time 11.12 mins. (5-95-13 method).
Reaction SMILES: CO[C:3]1[CH:4]([CH:10]=[CH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[Cl-:22].[NH4+:23]>CO>[ClH:22].[NH:23]=[C:3]1[CH:4]([CH:10]=[CH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9]1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC(=O)c1ccccc1C=CC1CCCCN=C1OC
Solvent: CO
Product: COC(=O)c1ccccc1C=CC1CCCCNC1=N
Product: Cl

Procedure:
The title product of Example 86 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:31]([O:35][C:36](=[O:44])[CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]1)([CH3:34])([CH3:33])[CH3:32].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[C:31]([O:35][C:36](=[O:44])[CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH:43][C:8](=[O:9])[C@@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:21])([F:22])[F:23])[C:12]2=[O:24])[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:39]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol, prepared as in Example 1) in methylene chloride (4 mL) and N,N-dimethylformamide (4 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (4 mL) and then added dropwise to a separate reaction flask containing a mixture of (3-amino-pyrazol-1-yl)-acetic acid tert-butyl ester (prepared as in US 20080021032, Example 3, 86 mg, 0.44 mmol) and 2,6-lutidine (100 μL, 0.87 mmol) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then quenched by the addition of methanol and then diluted with methylene chloride. The organic layer was then concentrated in vacuo with silica gel (2.0 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester (151 mg, 100%) as a white foam: HR-ES(+) m/e calcd for C26H31N4O4F3 [M+H]+ 521.2370, observed 521.2368; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.49 (s, 1H), 8.08 (d, J=7.46 Hz, 1H), 7.81 (d, J=7.67 Hz, 1H), 7.63 (t, J=7.67 Hz, 1H), 7.33 (d, J=2.34 Hz, 1H), 6.73 (d, J=2.34 Hz, 1H), 5.02 (dd, J=7.03, 8.52 Hz, 1H), 4.70-4.81 (m, 1H), 4.53-4.69 (m, 3H), 1.10-2.25 (m, 20H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH:13]([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([CH3:15])[CH3:14].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[CH:13]([N:16]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([O:11][CH3:12])[CH:4]=1)([CH3:15])[CH3:14]
Reactant: COc1cc(C(=O)O)ccc1Br
Reactant: CC(C)NC1CCCCC1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromo-3-methoxybenzoic acid (2.80 g, 12.1 mmol) in thionyl chloride (30 mL) was refluxed for 3 hr. The reaction was concentrated in vacuo and the residue azeotroped three times with toluene. A solution of the resulting crude solid (3.11 g, 8.75 mmol) in THF (10 mL) was added to a stirred, cold (0° C.) solution of N-isopropylcyclohexyl amine (1.7 g, 11.7 mmol) and triethylamine (1.20 g, 11.7 mmol) in THF (10 mL). The reaction was stirred at room temperature overnight. The reaction was filtered and the filtrate diluted with ethyl acetate and washed three times with 1N HCl, three times with saturated NaHCO3, three times with saturated NaCl solution and dried (Na2SO4). The drying agent was filtered and the filtrate concentrated in vacuo to give a dark brown oil. The oil was purified by chromatography on silica gel using mixtures of ethyl acetate and hexane as eluents. This yielded crystalline amide, m. p. 104-107° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:22][C:23]2[CH:24]=[N:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]([CH2:18][C:19]([OH:21])=O)[CH2:16][N:17]=1)=[CH:9]2)[CH3:2].[NH4+].O[N:35]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:22][C:23]2[CH:24]=[N:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]([CH2:18][C:19]([NH2:35])=[O:21])[CH2:16][N:17]=1)=[CH:9]2)[CH3:2]
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 0 °C
Yield: 88.6 %

Procedure:
To an ice-cooled and stirred mixture of [2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (95 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole ammonium salt (61 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg). After stirring at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give a pale yellow amorphous solid, which was crystallized from ethyl acetate-hexane to give the title compound (84 mg) as colorless crystals. Recrystallization from ethyl acetate-hexane gave the title compound (71 mg, 76%) as colorless crystals. MS 475 (MH+). mp 195-196° C.