Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[N:11]([CH2:12][C:13]([N:15]([CH2:22][CH:23]([NH2:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:16][C:17]([O:19]CC)=[O:18])=[O:14])[C:10]2[NH:9][C:8]3[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=3[S:6][C:5]=2[CH:4]=[N:3]1.[Li+].[OH-].O>C1COCC1>[OH:1][CH:2]1[N:11]([CH2:12][C:13]([N:15]([CH2:22][CH:23]([NH2:31])[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:16][C:17]([OH:19])=[O:18])=[O:14])[C:10]2[NH:9][C:8]3[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=3[S:6][C:5]=2[CH:4]=[N:3]1
Reactant: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)CN1C2=C(C=NC1O)Sc1ccccc1N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(N)CN(CC(=O)O)C(=O)CN1C2=C(C=NC1O)Sc1ccccc1N2
Yield: 90.6 %

Procedure:
Ethyl N-[(2-hydroxy-10-H-pyrimido[5,4-b][1,4]benzothiazin-1-yl)acetyl]-N-(2-Boc-aminoethyl)glycinate (201 mg, 0.4 mmol) was dissolved in THF (10 mL) and LiOH (2M, aqueous, 1.0 mL) was added. After 15 minutes at room temperature water (10 mL) was added, the THF was evaporated in vacuo and HCl (2M, aqueous, 1.0 mL) was added with vigorous stirring. The solid yellow material was filtered off and dried in vacuo to give 173 mg (91%) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[CH:16]=NCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=O)C(O)=[O:28].CO>O1CCOCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[CH:16]=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)O
Reactant: Fc1cccc(NCc2ccccc2)c1C=NCc1ccccc1
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: O=Cc1c(F)cccc1NCc1ccccc1
Reaction time: 1 h
Yield: 786.3 %

Procedure:
To a solution of Example 1A (11.95 g, 3.9 mmol) in dioxane was added water (40 mL) until the solution just clouded and then dioxane was added until the solution became clear again(˜5 mL). Oxalic acid (9.83 g, 78.0 mmol) was added in a single portion to give a dark orange solution which became a thick slurry. To the slurry was added in sequence: water (110 mL), dioxane (60 mL), and methanol (20 mL). This gave a mostly homogeneous solution with some small crystals which eventually dissolved as the reaction mixture was stirred for 1 hour. The volume of the reaction was reduced to ⅓ of the original volume by concentration under vacuum. The resulting solution was extracted (3×, ethyl acetate). The organic extracts were combined and washed (2×, 10% aqueous HCl; 2×, saturated aqueous NaHCO3; 2×, brine), dried (Na2SO4), filtered and concentrated under vacuum to give a thick orange-yellow oil which was dried under vacuum at 45° C. to a constant weight providing the title compound (7.03 g, 79%) as a orange-yellow solid. This material was pure by 1H NMR. A small portion was recrystallized from ether/hexanes.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)[CH2:3]1.C[O:19][C:20]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[S:31](Cl)(=[O:33])=[O:32])[CH2:23]1)=[O:21]>>[CH3:1][C@H:2]1[CH2:3][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][N:9]=2)[CH2:5][CH2:6][N:7]1[S:31]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:29]=1[CH2:30][CH:22]([C:20]([OH:21])=[O:19])[CH2:23]2)(=[O:33])=[O:32]
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Product: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2

Procedure:
The compound 4-[2-(S)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (s, 1H), 7.82-7.76 (m, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.37 (t, 1H), 6.93-6.88 (m, 1H), 4.35-4.18 (m, 2H), 4.18-4.02 (m, 1H), 3.60-3.46 (m, 1H), 3.45-3.10 (m, 7H), 2.97-2.80 (m, 1H), 1.06-1.01 (m, 3H); MS (ESI): 470.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:24]=1[CH3:41].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:33][C:31]1[CH:30]=[C:29]([F:34])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:3]=1)=[C:24]([CH3:41])[C:25]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[N:26]2
Reactant: N#Cc1ccc(N)cc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1ccc(C#N)c(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 4-amino-2-morpholinobenzonitrile (46.5 mg, 0.23 mmol) in dry DMF (2.0 mL) was cooled to 0° C., then potassium tert-butoxide (78.8 mg, 0.70 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 minutes, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (74.7 mg, 0.26 mmol) was added in portions. Upon complete addition, the mixture was warmed to 100° C. After 2.5 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:methanol (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:methanol:ammonium hydroxide in DCM) to afford a yellow film that was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concd then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 4-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-2-morpholinobenzonitrile. 1H NMR (500 MHz, CDCl3) δ ppm 8.74 (1H, d, J=4.6 Hz), 7.97 (2H, m), 7.72 (1H, m), 7.47 (1H, d, J=8.3 Hz), 7.44 (1H, m), 7.11 (2H, m), 6.44 (2H, m), 3.96 (4H, m), 3.26 (4H, m), 2.24 (3H, s). Mass Spectrum (pos.) m/e: 458.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:27][CH2:26][CH2:25][C@H:8]3[S:9](=[O:24])(=[O:23])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][C@:7]3([CH3:28])[C:6]=2[CH:29]=1.[Cl:30][C:31]1[N:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1>>[Cl:30][C:31]1[N:32]=[CH:33][C:34]([C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:27][CH2:26][CH2:25][C@H:8]4[S:9](=[O:23])(=[O:24])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[N:12][C@:7]4([CH3:28])[C:6]=3[CH:29]=2)=[O:38])=[N:35][CH:36]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(NC(=O)c4cnc(Cl)cn4)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Yield: 70.1 %

Procedure:
Using general method 3 (step 1), trans intermediate 19 (150 mg, 0.354 mmol) and 5-chloropyrazine-2-carboxylic acid (67.4 mg, 0.425 mmol) were combined to afford the title compound (140 mg, 0.248 mmol, 70.1%) as a white solid. MS m/z=564.0 (M+H).
Reaction SMILES: C[CH:2]([C:4]1C=CC=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[S:49]1C=CC(CC(O)=O)=C1>>[S:49]1[CH:2]=[CH:4][C:5]([CH2:13][C:14]([C:16]2[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)=[O:15])=[CH:6]1
Reactant: O=C(O)Cc1ccsc1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)Cc2ccsc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as 5 for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 3-thiopheneacetic acid, mp 136°-138° C.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:20][C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(N(CC)CC)C.[H][H]>[Pd].C(O)C>[C:8]1([C:6]2[N:7]=[CH:2][C:3]3[NH:20][C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:4]=3[N:5]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Clc1nc(-c2ccccc2)nc2c1[nH]c1ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc(-c2ncc3[nH]c4ccccc4c3n2)cc1

Procedure:
A mixture of 4-Chloro-2-phenyl-5H-indolo[3,2-d]pyrimidine (650 mg), triethylamine (1.0 g), 10% palladium on carbon catalyst (110 mg) and ethanol (30 mL) was stirred under 1 atm of hydrogen for 1 h. The catalyst was filtered through celite and the ethanol is removed in vacuo. the residue is suspended in saturated ammonium chloride solution and the product was extracted with methylene chloride. After drying over magnesium sulfate the solvent was removed in vacuo to afford 2-Phenyl-5H-indolo[3,2-d]pyrimidine (Compound 4) after trituration with ether.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH2:12])[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:26]([NH:12][CH:5]1[CH:4]2[CH2:10][CH:8]3[CH2:9][C:2]([OH:1])([CH2:11][CH:6]1[CH2:7]3)[CH2:3]2)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC12CC3CC(C1)C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C3)C2
Reaction time: 0.17 h

Procedure:
5-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine (2.0 g; 0.012 mole) is dissolved in 70 ml of dichloromethane with gentle heating. To this is added triethylamine (2.4 g; 0.024 mole) and cooled in an ice bath. To this is added triphenylmethyl chloride (3.34 g ;0.012 mole) in dichloromethane (10 ml) all at once. The reaction is stirred for 10 minutes with ice cooling and then 5 hours at room temperature. The reaction mixture is heated to reflux overnight, cooled, filtered and evaporated to dryness. Purification is accomplished via HPLC (eluting with 20% ethyl acetate/hexane) to obtain N-trityl-5-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine (m.p. 166°-170° C.) which is used directly in step E.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[Cl:23][C:24]1[C:33]2[N:28]([C:29](=[O:51])[N:30]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37](B4OC(C)(C)C(C)(C)O4)[C:36]=3[CH3:50])[C:31](=[O:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([N:30]2[C:31](=[O:34])[CH:32]=[C:33]4[C:24]([Cl:23])=[CH:25][CH:26]=[CH:27][N:28]4[C:29]2=[O:51])[C:36]=1[CH3:50])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(Cl)cccn2c1=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)cc2c(Cl)cccn2c1=O
Temperature: 60 °C
Yield: 69.8 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (1.11 g, 2.91 mmol), 5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 33] (1.00 g, 2.42 mmol) and Cs2CO3 (1.58 g, 4.85 mmol) in THF (8 mL) and water (2 mL) was bubbled with argon for three min. The mixture was treated with PdCl2(dppf) DCM adduct (0.099 g, 0.121 mmol) and heated at 60° C. overnight. The cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with DCM containing a small amount of MeOH. The combined organic layers were dried and concentrated until a tan precipitate formed, which was removed by filtration. The filtrate was concentrated and purified by column chromatography on silica gel (120 g), eluting with EtOAc-DCM (sequentially 70%, 80%, and 100%), to give 3-chloro-4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a yellow solid (993 mg, 69% yield). The material was separated by chiral super-critical fluid chromatography as follows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO2-IPA (50:50) at 150 mL/min, 45° C., 100 bar; sample preparation: 5.6 mg/mL in MeOH-DCM (1:1); injection: 3 mL. The second peak eluting from the column provided 3-chloro-4-(R)-(3-(R)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Example 32]. Mass spectrum m/z 587 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.27 (s, 2H), 8.14 (s, 1H), 7.84 (d, J=1.1 Hz, 1H), 7.59 (d, J=6.8 Hz, 1H), 7.56-7.46 (m, 2H), 7.29 (dd, J=7.4, 1.2 Hz, 1H), 7.01 (dd, J=8.4, 1.5 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 6.55 (t, J=7.3 Hz, 1H), 5.98 (s, 1H), 5.75 (s, 1H), 4.98 (s, 1H), 1.71 (s, 3H), 1.46-1.42 (m, 6H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][CH:12]([N:17]1[C:30]3[CH:29]=[CH:28][C:27]([C:31](O)=[O:32])=[CH:26][C:25]=3[O:24][C:23]3[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:58]([N:60](CC)[CH2:61][CH3:62])[CH3:59]>CN(C=O)C>[CH2:58]([N:60]([CH2:61][CH3:62])[C:31]([C:27]1[CH:28]=[CH:29][C:30]2[N:17]([CH:12]3[CH2:13][CH:14]4[N:9]([CH3:8])[CH:10]([CH2:16][CH2:15]4)[CH2:11]3)[C:18]3[C:23]([O:24][C:25]=2[CH:26]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:32])[CH3:59]
Reactant: CCN(CC)CC
Reactant: CN1C2CCC1CC(N1c3ccccc3Oc3cc(C(=O)O)ccc31)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of the TFA salt of 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid 3a (65 mg, 0.14 mmol) and HBTU (64 mg; 0.17 mmol) in DMF (2 mL) was added triethylamine (69 μL, 0.43 mmol). The mixture was stirred for 1 hr at rt, and purified without prior quenching via reverse phase HPLC (eluent gradient: acetonitrile in water containing 0.1% TFA) to yield 44.4 mg (61%) of title compound 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 4a as a TFA salt. MS m/z (MH+) 406.2.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)/[CH:5]=[CH:6]/[CH3:7]>CO.[Pd]>[OH:1][CH2:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:5][CH2:6][CH3:7]
Reactant: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCC[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.03 h
Yield: 98.8 %

Procedure:
tert-Butyl (2S,3S,E)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (0.51 g, 1.4 mmol) was taken up in 10 mL of MeOH. 0.10 g of 10% Pd on carbon was added, and hydrogen was bubbled through the mixture. After 2 minutes, the bubbling ceased and the reaction was kept under a balloon of hydrogen. After 2 hours, the mixture was filtered through celite and concentrated under reduced pressure, affording tert-butyl (2S,3S)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)hexan-2-ylcarbamate (0.50 g, 97% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:10](=[O:13])[CH2:11]C)=[CH:5][CH:4]=1)#[N:2].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:10](=[O:13])[CH3:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCC(=O)N(c1ccc(C#N)cc1)c1c(NC(C)C(C)(C)C)c(=O)c1=O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(c1ccc(C#N)cc1)c1c(NC(C)C(C)(C)C)c(=O)c1=O
Reaction time: 24 h

Procedure:
The intermediate of Example 1, second paragraph (1.0 g, 3.36 mmol), acetic anhydride (0.95 mL, 10.0 mmol), and pyridine (10 mL) were mixed and allowed to stand at room temperature for 24 hours. The reaction mixture was filtered, and the solid was washed with ethyl acetate yielding 0.84 g (76%) of a yellow solid: mp 284°-286° C. (dec); 1H NMR (CDCl3): δ 7.82 (d, 2H), 7.47 (d, 2H), 7.38 (br d, 1H), 4.27 (dq, 1H), 2.02 (s, 3H), 1.25 (d, 3H), 0.99 (s, 9H). IR (KBr): 3358, 2978, 2236, 1804, 1739, 1685, 1614 cm-1 ; MS (m/z) 339 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3)[CH:10](O)[CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: OC1CC(c2ccc(F)cc2)c2ccc(F)cc21
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1ccc(C2CC(Cl)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 52 grams of 3-(4'-fluorophenyl)-6-fluoro-1-indanol in 250 milliliters of dry toluene was cooled in ice water, and a solution of 21 milliliters of thionylchloride in 21 milliliters of toluene was added dropwise keeping the reaction temperature below 10 degrees Centigrade. The reaction mixture was stirred at room temperature for 30 minutes and then slowly heated to 60 degrees Centigrade in a water-bath and kept at this temperature for one hour. The reaction mixture was then treated with ice-water, extracted with an aqueous sodium carbonate solution and dried over anhydrous magnesium sulfate. After filtration and evaporation in vacuo there was obtained 55 grams of crude 1-chloro-3-(4'-fluorophenyl)-6-fluoroindane, which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([O:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([O:17][C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:25][CH:26]=1)=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl bromoacetate (15.5 ml) was added dropwise over 10 minutes to a mixture of the product of step (a) (21 g), anhydrous potassium carbonate (20 g) and acetone (450 ml). On completion of the addition the reaction mixture was stirred at ambient temperature overnight. Insoluble material was removed by filtration and the filtrate was evaporated to dryness. The solid residue was crystallised from ethyl acetate to give t-butyl 4-benzyloxycarbonylaminophenoxyacetate (25.1 g) as a white solid: m.p. 109°-110° C.; NMR Spectrum (DMSO-d6) 1.42 (9H, s), 4.56 (2H, s), 5.12 (2H, s), 6.82 (2H, d), 7.31-7.43 (7H, m), 9.54 (1H, br s).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[NH3:24]>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:24])=[O:2])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)CC(=O)Nc1ccc(CCc2ccc(F)cc2)cc1
Reactant: N
Solvent: CO
Product: NC(=O)CC(=O)Nc1ccc(CCc2ccc(F)cc2)cc1
Yield: 94 %

Procedure:
Prepared in analogy to example 3 from N-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield=94%. Colorless solid. MS: m/e=301.1 (M++H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:7]([OH:8])[C@@H:6]([CH2:9][OH:10])[O:5][C@H:4]1[N:11]1[C:20]2[N:19]=[CH:18][N:17]=[C:15](N)[C:14]=2[N:13]=[CH:12]1.[N+]([O-])([O-])=[O:22].[Na+]>C(O)(=O)C>[CH3:1][O:2][C@@H:3]1[C@H:7]([OH:8])[C@@H:6]([CH2:9][OH:10])[O:5][C@H:4]1[N:11]1[C:20]2[N:19]=[CH:18][N:17]=[C:15]([OH:22])[C:14]=2[N:13]=[CH:12]1
Reactant: O=[N+]([O-])[O-]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Agent: [Na+]
Solvent: CC(=O)O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(O)ncnc21
Reaction time: 24 h

Procedure:
Deamination of 2'-O-methyladenosine was accomplished by a modified procedure of Iwai et al., Anomeric 9-D-Glucopyranosyl-adenines and 9-D-Glucopyranosyl-hypozanthines, in Synthetic Procedures in Nucleic Acid Chemistry 135-142 (Zorbach & Tipson eds., Interscience Publishers, New York, N.Y., 1965). To a solution of 2'-O-methyladenosine (6.61 g, 23.5 mmol) dissolved in 4.4% aqueous acetic acid was added 13.1 g sodium nitrate (190 mmol). This reaction solution was stirred 24 hours in a foil covered vessel and thereafter evaporated to dryness in vacuo. The product was desalted with Amberlite XAD-4 resin and recrystallized in methanol. FABMS (glycerol) m/z 284 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Brc1ccccn1
Reactant: O=Cc1ccccc1O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1ccccc1Oc1ccccn1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A solution of 2-hydroxybenzaldehyde (10.00 g, 81.9 mmol), 2-bromopyridine (26.91 g, 170.3 mmol), potassium carbonate (17.54 g, 126.9 mmol), and copper (2.60 g, 40.95 mmol) in pyridine (80 mls) was refluxed for 3 days. The reaction was then cooled to r.t., filtered through Celite, diluted with ethylacetate (500 mls) and washed with water (3×300mls). The organic was then dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, 9:1 hexanes:ether) to afford 16.21 g (99%)of 2-(2-pyridyloxy)benzaldehyde as a yellow oil.