Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][C:23]([CH3:37])([CH2:26][O:27][CH2:28][CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][OH:25].C(OCC)C>C(Cl)Cl>[CH3:22][C:23]([CH3:37])([CH2:26][O:27][CH2:28][CH:29]=[CH:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH:24]=[O:25]
Reactant: CC(C)(CO)COCC=Cc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C=O)COCC=Cc1ccccc1

Procedure:
In a dry three-neck flask equipped with a mechanical stirrer and an addition funnel was placed 128 g of pyridinium dichromate and 320 ml of dry CH2Cl2. The mixture was vigorously stirred and a solution of 32.37 g (0.147 mole) of 2,2-dimethyl-3-(3-phenyl-2-propenoxy)propanol, the product of Example 10a, in 50 ml of CH2Cl2 was added in one portion. The reaction mixture was stirred at room temperature for three days and then was poured into 400 ml of ethyl ether. The resulting mixture was filtered through a column packed with dry silica gel to obtain a yellow filtrate. The filtrate was concentrated to obtain a yellow residue. Kugelrohr distillation of the residue gave the title compound, bp 90°/0.05 mm Hg.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:8]1=[O:18])=[O:5].FC(F)(F)C([O-])=O.[CH2:28]([O:35][C@H:36]([CH3:39])[CH:37]=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(=O)[C@@H](C)O)C>>[CH2:28]([O:35][C@H:36]([CH3:39])[CH2:37][NH:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:8]1=[O:18])=[O:5])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@H](C=O)OCc1ccccc1
Reactant: CC(C)(N)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Agent: CCOC(=O)[C@@H](C)O
Agent: O=C([O-])C(F)(F)F
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1

Procedure:
Prepared from 3-amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide, trifluoroacetate (Example 107, Step C) and (R)-2-benzyloxypropanal (prepared from ethyl-D-lactate according to the procedure of Hanessian and Kloss, Tetrahedron Lett. 1985, 26, 1261-1264.) by the procedure described in Example 86, Step A. 1H NMR (200 Mhz,CD3OD): 1.31 (d,6 Hz,3H), 1.40 (s,3H), 1.43 (s,3H), 2.17 (m,1H), 2.30 (m,1H), 2.6-3.1 (m,5H), 3.22 (dd;3,12 Hz;1H), 3.86 (m,1H), 4.48 (dd;7,12 Hz;1H), 4.50 (d,12 Hz,1H), 4.70 (d,12 Hz,1H), 7.11 (d,8 Hz,1H), 7.15-7.45 (m,8H). FAB-MS: calculated for C25H33N3O3 423; found 424 (M+H,100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:38])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:21]=2[N:20]([CH3:36])[C:19]1=[O:37])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:38])[N:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:21]=3[N:20]([CH3:36])[C:19]2=[O:37])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2)c2cc(Cl)ccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2)c2cc(Cl)ccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-C), the title compound was prepared as a white solid having a melting point of 126.5–130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[N:24][N:23]=2)=[C:20]2[C:15]([N:16]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:17](=[O:29])[NH:18][C:19]2=[O:28])=[N:14]1.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[N:24][N:23]=2)=[C:20]2[C:15]([N:16]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:17](=[O:29])[N:18]([CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[C:19]2=[O:28])=[N:14]1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3nncn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21
Product: CC(C)Cn1c(=O)n(CCN2CCOCC2)c(=O)c2c(-c3nncn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was made by alkylation of 2-[(6-chloroquinolin-4-yl)methyl]-7-isobutyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione with 4-(2-chloroethyl)morpholine following conditions in Example 6.d. 578.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:18][OH:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Solvent: C1CCOC1
Product: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 29.1, [rac]-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was reduced using borane-tetrahydrofuran complex in THF to give the title compound as off-white solid. MS: m/e=359.2 [M+H+].
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[F:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](Cl)=[O:27])=[CH:22][C:21]=1[CH3:31].[NH4+].[Cl-]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:26](=[O:27])[CH2:25][O:24][C:23]1[CH:29]=[CH:30][C:20]([F:19])=[C:21]([CH3:31])[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: Cc1cc(OCC(=O)Cl)ccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)ccc1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To the solution of (S)-4-Benzyl-2-oxazolidinone (857 mg, 4.8 mmol) in anhydrous 30 mL THF at −70° C. was slowly added n-BuLi (3.0 mL, 4.8 mmol, 1.6 M in hexane) over 15 minutes. The reaction mixture was stirred for 30 min at −70° C. and to it was slowly added a solution of 2-(4-fluoro-3-methylphenoxy)acetyl chloride crude solution in 4 mL THF. The resulting mixture was stirred at −70° C. for 2 h and the temperature was slowly raised over a period of 1 h. The mixture was poured into 30 mL saturated NH4Cl and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluting with 0% to 50% ethyl acetate/hexane to give 1.5 g of the title compound as a light yellow oil.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[C:15]2[O:16][CH:17]=[C:18]([C:20](OC)=[O:21])[N:19]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:5]1([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14]=2[C:15]2[O:16][CH:17]=[C:18]([CH2:20][OH:21])[N:19]=2)[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: COC(=O)c1coc(-c2c(-c3ccccc3)cnnc2-c2cccc(OC)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of compound 26 (20 mg, 0.056 mmol) in THF (3 mL), LAH (5.0 mg, 0.14 mmol) was added at −30° C. and stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution at −30° C. The reaction mixture was slowly warmed to rt and filtered through celite bed, washed with ethyl acetate. The organic layer was washed with brine, dried over anhy. Na2SO4 and concentrated under reduced pressure to obtain the crude product gave (2-(3,5-diphenylpyridazin-4-yl)oxazol-4-yl)methanol (16 mg, 88%) as an yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH:10]=O)=[CH:4][CH:3]=1.C1(P(=CC=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O:50][CH2:51][CH3:52])(=O)C.[Br-].[Li+]>C1(C)C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH:10]=[CH:52][CH:51]=[O:50])=[CH:4][CH:3]=1
Reactant: Cn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 86.6 %

Procedure:
A mixture of 448 g (1.37 mol) of 3,3-bis(4-flurophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal and 445 g (1.46 mol) of triphenylphosphoranylidene acetaldehyde in 5.5 L of toluene was heated with stirring to 55° C. After turning off the heat source, the temperature rose to 62° C. After 20 minutes, heat was applied and 60° C. was maintained for 30 minutes. Analytical TLC indicated that the reaction was complete (50% ethyl acetate in hexane). Lithium bromide (128 g, 1.47 mol) was added and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 900 mL of boiling absolute ethanol. To this solution was slowly added 900 mL of hexane. After 16 hours at ambient temperature and 2 hours at cold freezer temperature, the mixture was filtered to give 418 g (86.6%) of the title compound; m.p.=161°-165° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[CH:22]=1)=[O:5]
Reactant: COc1cc(N)ccn1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (25 g, 110.3 mmol) in dichloromethane (125.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8 mL, 330.9 mmol) and dichloromethane (500.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)benzamide (33.6 g, 97.00%) as an off-white solid. ESI-MS m/z calc. 314.07. found 315.2 (M+1)+; Retention time: 1.44 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.12-8.07 (m, 2H), 8.07-7.98 (m, 1H), 7.65 (t, J=9.2 Hz, 1H), 7.24-7.19 (m, 2H), 3.85 (s, 3H) ppm.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1.[CH3:14]I>CN(C=O)C.O>[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]2[N:9]([CH3:14])[CH:10]=[N:11][C:7]=2[CH:6]=1
Reactant: CI
Reactant: COc1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)ncn2C
Reaction time: 0.08 h
Yield: 54.8 %

Procedure:
To a solution of NaH (972 mg, 40.5 mmol) in DMF (20 mL) was added 5-methoxy-1H-benzo[d]imidazole (2.0 g, 13.5 mmol) at 27° C. After stirring for 5 minutes, MeI (2.3 g, 16.2 mmol) was added and the resulting mixture was stirred for 16 h. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the crude product (1.2 g, 54.5%) as a grown solid. This crude was used in next step without further purification. LCMS (m/z): 163.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[C:4](/[CH:14]=[N:15]/O)[CH:3]=1>C([O-])(=O)C.[Zn]>[NH2:15][CH2:14][C:4]1[CH:3]=[C:2]([F:1])[C:10]2[C:9]([CH3:11])([CH3:12])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=1
Reactant: CC1(C)OB(O)c2cc(/C=N/O)cc(F)c21
Agent: CC(=O)[O-]
Agent: [Zn]
Product: CC1(C)OB(O)c2cc(CN)cc(F)c21
Temperature: 42.5 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde oxime (1.8 g, 8.57 mmol) in acetate acid (18 mL) at rt was added Zn powder (2.8 g, 42.85 mmol). The reaction mixture was stirred at 40 to 45° C. for 3 h. The mixture was cooled to rt, filtered and concentrated under reduced pressure give crude 6-(aminomethyl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol as white solid. It was used in next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:34])=[C:24]([NH:27][C:28]([NH:30][CH:31]3[CH2:33][CH2:32]3)=[O:29])[CH:25]=2)[NH:20][C:19](=[O:35])[C:18]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Br:42][C:38]1[CH:37]=[C:36]([C:18]2[C:19](=[O:35])[NH:20][C:21]3[C:26]([C:17]=2[O:16][CH2:15][CH2:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]2)=[CH:25][C:24]([NH:27][C:28]([NH:30][CH:31]2[CH2:33][CH2:32]2)=[O:29])=[C:23]([Cl:34])[CH:22]=3)[CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccc(Br)c2)c(=O)[nH]c2cc(Cl)c(NC(=O)NC3CC3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(Nc1cc2c(OCCC3CCCCN3)c(-c3cccc(Br)c3)c(=O)[nH]c2cc1Cl)NC1CC1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To a solution of 2-{2-[3-(3-bromophenyl)-7-chloro-6-(3-cyclopropyl-ureido)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (14 mg in 2.0 mL methylene chloride) was added 2 drops of anisole followed by 2.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 30 minutes the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 95:5:1; then 90:10:1) to give the title compound (6.0 mg).
Reaction SMILES: COC(=O)C[C@H]1C2C=CC(O[C@H]3C4C(=C(C5C(Br)=NC=CC=5)C=CC=4F)CC3)=CC=2OC1.CN1C(C)=C(B2OC(C)(C)C(C)(C)O2)C(C)=N1.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1.C[O:77][C:78](=[O:114])[CH2:79][C@H:80]1[C:84]2[CH:85]=[CH:86][C:87]([O:89][C@H:90]3[C:98]4[C:93](=[C:94]([C:100]5[C:101]([C:106]6[C:107]([CH3:113])=[N:108][N:109]([CH3:112])[C:110]=6[CH3:111])=[N:102][CH:103]=[CH:104][CH:105]=5)[CH:95]=[CH:96][C:97]=4[F:99])[CH2:92][CH2:91]3)=[CH:88][C:83]=2[O:82][CH2:81]1>>[F:99][C:97]1[CH:96]=[CH:95][C:94]([C:100]2[C:101]([C:106]3[C:107]([CH3:113])=[N:108][N:109]([CH3:112])[C:110]=3[CH3:111])=[N:102][CH:103]=[CH:104][CH:105]=2)=[C:93]2[C:98]=1[C@H:90]([O:89][C:87]1[CH:86]=[CH:85][C:84]3[C@H:80]([CH2:79][C:78]([OH:114])=[O:77])[CH2:81][O:82][C:83]=3[CH:88]=1)[CH2:91][CH2:92]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5-c5c(C)nn(C)c5C)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5Br)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Agent: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Product: Cc1nn(C)c(C)c1-c1ncccc1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-4-(2-bromo-pyridin-3-yl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole following a procedure analogous to that described in Step 5 of Intermediate 1. Saponification of the methyl ester, {(S)-6-[(R)-7-fluoro-4-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-pyridin-3-yl]-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester, following a procedure analogous to that described for Example 4 gives the title compound; if the title compound does not precipitate from the aqueous solution, the crude title compound is purified by HPLC. LC (method 9): tR=0.88 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C1(C2[O:26]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16]([CH3:17])=[O:26])[N:8]=3)[CH2:2][CH:3]([CH2:5]1)[CH2:4]2
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a stirring solution of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylthio)pyrimidine-5-carboxamide (76 g, 0.304 mol) in chloroform (7 L) was added 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (143 g, 0.547 mol, 1.8 equiv.) and the resulting pale yellow solution was stirred at ambient temperature overnight. The reaction solution was concentrated under reduced pressure to give the crude product as a white solid, which was diluted with ethyl acetate (1.5 L) and the slurry was stirred at room temperature for 1 h. The resulting suspension was filtered, washed with ethyl acetate, and dried under vacuum to afford the desired compound (73 g, 0.274 mol, 90% yield) as a white solid; MS (ESI): m/z 267.0 [M+1]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:34][C:35]1[CH:44]=[C:43]2[C:38]([CH2:39][CH2:40][C:41](=[O:45])[NH:42]2)=[CH:37][CH:36]=1.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56](O)[CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>O1CCCC1>[O:45]=[C:41]1[CH2:40][CH2:39][C:38]2[C:43](=[CH:44][C:35]([O:34][CH:56]3[CH2:57][CH2:58][N:53]([C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])[CH2:54][CH2:55]3)=[CH:36][CH:37]=2)[NH:42]1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.9 %

Procedure:
Triphenylphosphine (0.577 g, 2.2 mmol) was dissolved in dry tetrahydrofuran (20 mL) under argon and the solution cooled to 0–5° C. Diisopropyl azodicarboxylate (0.404 g, 2 mmol) was added dropwise and the mixture stirred at 0–5° C. for 20 min. before addition of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one (0.326 g, 2 mmol) and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.402 g, 2 mmol). The resulting mixture was stirred at ambient temperature for 18 h then evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with a gradient of ethyl acetate in 60–80° C. petroleum ether, gave the title compound (0.2 g, 29%) as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([I:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33]N1C(=O)CCC1=O>CN(C=O)C>[Cl:33][CH2:2][C:3]1[C:4]([I:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCc1cc2ccccc2nc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: ClCc1cc2ccccc2nc1I
Temperature: -23 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a stirred mixture of 3-hydroxymethyl-2-iodoquinoline prepared in accordance with Example 10 above (350 mg, 1.23 mmol) and triphenylphosphine (483 mg, 1.84 mmol) in 10 mL of dry DMF at -23° C. was added N-chlorosuccinimide (246 mg, 1.84 mmol), and the mixture was stirred for 1 h at -23° C. After the addition of 40 mL of dilute aqueous NaHCO4, the mixture was extracted with ethyl acetate (20 mL) and then ether (2×15 mL). The combined organic extracts were washed successively with 20-mL portions of dilute NaHCO4, water and brine, and were dried over MgSO4. Concentration and purification of the residue by radial PLC (silica gel, 10% ethyl acetate/hexanes) afforded 312 mg (84%) of 3-chloromethyl-2-iodoquinoline as a white crystalline solid: mp 138°-140° C. Recrystallization from hexanes afforded an analytical sample as colorless needles: mp 139°-140° C. 1H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H), 8.07 (d, 1H, J=9 Hz), 7.84 (d, 1H, J=9 Hz), 7.75 (t, 1H, J=9 Hz), 7.62 (t, 1H, J=9 Hz), 4.80 (s, 1H); IR (nujol) 1585, 1555, 1260, 1010, 780, 755, 710 cm-1.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[CH:10]([CH3:13])[CH2:11][NH2:12])[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.CCN(CC)CC.CCOC(C)=O>CC(O)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:12][CH2:11][CH:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]3[CH2:3][CH2:2][O:1][C:9]=23)[CH3:13])[CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(CN)c1ccnc2c1OCC2
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(CNc1cc(Cl)ncn1)c1ccnc2c1OCC2
Temperature: 80 °C
Yield: 81 %

Procedure:
As shown in step 6-iv of Scheme 6, to a suspension of 2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propan-1-amine.2HCl and 4,6-dichloropyrimidine (456.0 mg, 3.061 mmol) in i-PrOH (17.01 mL) was added Et3N (1.291 g, 1.778 mL, 12.76 mmol). The reaction mixture was heated at 80° C. for 2 h, cooled to room temperature, and partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous layer was further extracted with EtOAc (2×50 mL) and the combined organics were washed with H2O (50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc/hexanes, then isocratic EtOAc) to afford 6-chloro-N-(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)pyrimidin-4-amine (600.3 mg, 81% yield over two steps). Chiral SFC purification (20% MeOH at 5 mL/min on a ChiralPak® AD-H (4.6 mm×100 mm) column, 100 bar, 35° C., 220 nm) provided (S)-6-chloro-N-(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)pyrimidin-4-amine (Compound 2021, 300 mg, SFC retention time 1.05 minutes): LCMS=291.04 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.00 (d, J=4.5 Hz, 1H), 6.92 (d, J=4.4 Hz, 1H), 6.36 (s, 1H), 5.24 (s, 1H), 4.71 (t, J=8.9 Hz, 2H), 3.61-3.35 (m, 4H), 3.23 (dd, J=14.0, 6.9 Hz, 1H), 1.35 (d, J=6.9 Hz, 3H). The corresponding (R)-enantiomer had a retention time of 1.25 minutes).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.Cl.CO>O>[OH:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccc(O)c1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2cccc(O)c2)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 56 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 3-hydroxybenzaldehyde 0.903 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for one hour and cooled to room temperature, and water 400 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for six hours under reduced pressure to obtain the desired compound 0.92 g.