Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]=O.[C:9](#[N:13])[CH2:10][C:11]#[N:12]>C(O)C.N1CCCCC1>[NH2:13][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][C:6]2=[CH:7][C:10]=1[C:11]#[N:12]
Reactant: Nc1sccc1C=O
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1cc2ccsc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
2-Amino-thiophene-3-carbaldehyde described in Preparation Example T-4 (38 mg, 0.30 mmol) and malononitrile (20 mg, 0.30 mmol) were dissolved in ethanol (1 mL) to which piperidine (several drops) had been added, and the solution was stirred for 1 hour under reflux. The reaction solution was cooled to room temperature, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (50 mg, 0.29 mmol, 96%) was obtained as a white solid.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl:6][SiH:7]([Cl:9])[Cl:8].C(O)(C)C>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:1]1([Si:7]([Cl:9])([Cl:8])[Cl:6])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCC1
Reactant: Cl[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: Cl[Si](Cl)(Cl)C1CCCC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
In a 100 ml autoclave were charged 16.7 g (0.245 mole) of cyclopentene, 30.1 g (0.222 mole) of trichlorosilane and 25 μl of a 0.077 m mole/ml chloroplatinic acid solution in isopropyl alcohol (platinum content 1.92×10-6 mole), which were then stirred at 150° C. for 30 minutes. Cyclopentyl trichlorosilane was obtained quantitatively.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Mn]([O-])(=O)(=O)=[O:19].[K+].[OH2:24]>CC(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:19])=[O:24])=[N:4][C:3]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[C:10]=1[F:17]
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(F)c(-c2cc(F)cc(F)c2F)n1
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(F)c(-c2cc(F)cc(F)c2F)n1
Temperature: 90 °C
Yield: 89 %

Procedure:
To a solution of 3-fluoro-6-methyl-2-(2,3,5-trifluorophenyl)pyridine (1.0 equiv.) in water and t-BuOH (2:1, 0.06 M) was added potassium permanganate (10 equiv.) and the solution was heated at 90° C. for 5 hours. Upon cooling to room temperature, the solution was filtered, and the filtrate was concentrated under reduced pressure to yield 5-fluoro-6-(2,3,5-trifluorophenyl)picolinic acid in 89% yield. LC/MS=272.0 (M+H), Rt=0.80 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:15][CH:16]([OH:33])[CH:17]([NH:25]C(OC(C)(C)C)=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35]>CO.C(O)(C)C>[Cl-:35].[CH2:18]([CH:17]([NH3+:25])[CH:16]([OH:33])[CH2:15][N:10]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:34])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cl
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: CC(C)O
Solvent: CO
Product: CC(C)CN(CC(O)C([NH3+])Cc1ccccc1)C(=O)OCc1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 64 h

Procedure:
(3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamic acid benzyl ester (3) (34.30 g, 72.90 mmol, 1 equiv) was dissolved in methanol (170 mL), followed by the addition of 5-6 N HCl in isopropanol (75 mL). The solution was stirred at room temperature for 64 h. Volatiles were evaporated under reduced pressure. The crude product was coevaporated with ethyl acetate (150 mL) to obtain 4 as a white solid (29.70 g, 72.90 mmol, quantitative). LRMS (ES+): m/z 371 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.C[O:14][C:15](=O)[CH2:16][CH2:17][CH2:18][NH2:19].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:19]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(=O)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCN1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 50.6 %

Procedure:
Dissolve 1,4-dioxaspiro{4.5}decan-8-one (100 g, 640.3 mmol), methyl-4-aminobutyrate hydrochloride (98.5 g, 640.3 mmol), triethylamine (90 mL, 640.3 mmol) and dichloromethane (2 L) and stir at room temperature. Add Sodium triacetoxyborohydride (135.7 g, 640.3 mmol) stir 17 h at room temperature. Quench with water (1 L), separate, wash the aqueous layer with dichloromethane (3×500 mL), combine the organic phases and dry over anhydrous sodium sulfate, filter and concentrate. Purify the material on a 1.5 kg silica column, 6 inches in diameter, and eluted with 8:2 hexanes/ethyl acetate to 95:5 ethyl acetate/methanol to give 73 g of the title compound as a waxy brown solid. 1H NMR (CDCl3) δ 3.99-4.10 (m, 1H), 3.93 (s, 4H), 3.32-3.36 (m, 2H), 2.36-2.40 (m, 2H), 1.94-2.03 (m, 2H), 1.65-1.83 (m, 8H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CO[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](I)[CH:12]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[C@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C@H:26]2[C@@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[O:18])[CH:12]=4)[C:29]3=[O:37])[CH2:27]2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cccc(I)c1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: CN1CCN(C(=O)c2cccc(N3C(=O)[C@@]4(C[C@H]4c4ccc(Cl)cc4)c4ccccc43)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 85 starting from 1-methylpiperazine, methyl-3-iodobenzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C28H26ClN3O2: 471, observed (M+H)+: 472.21H NMR (400 MHz, MeOD-d4) δppm 2.34 (dd, J=9.09, 5.05 Hz, 1 H) 2.43 (dd, J=8.59, 5.05 Hz, 1 H) 2.93 (s, 3 H) 3.17 (br. s., 4 H) 3.40 (t, J=8.84 Hz, 1 H) 3.62 (br. s., 4 H) 6.97 (d, J=7.83 Hz, 1 H) 7.16-7.25 (m, 2 H) 7.26-7.38 (m, 5 H) 7.49 (s, 1 H) 7.55 (t, J=7.71 Hz, 2 H) 7.67 (t, J=7.83 Hz, 1 H).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH2:20]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH2:20]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(Cc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 4-benzyl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C25H26O5 [M+Na]+: 429.3.
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:6](=[O:13])[O:7][C:8]([CH3:12])=[CH:9][C:10]=1[OH:11])[CH:2]=[CH2:3].[OH:14]O>C(O)(=O)C>[CH2:1]([S:4]([C:5]1[C:6](=[O:13])[O:7][C:8]([CH3:12])=[CH:9][C:10]=1[OH:11])=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCSc1c(O)cc(C)oc1=O
Reactant: OO
Solvent: CC(=O)O
Product: C=CCS(=O)c1c(O)cc(C)oc1=O
Temperature: 25 °C

Procedure:
3-Allylthio-4-hydroxy-6-methyl-2-pyrone (5.95 g., 0.0300 mol), 30% hydrogen peroxide (3.85 g., 0.0330 mol), and 40 ml. glacial acetic acid were combined and stirred over night at room temperature. The clear solution was poured into 250 ml. ice water. The aqueous mixture was extracted with clhoroform. The CHCl3 was dried (Na2SO4) and evaporated in vacuo. The recovered pink solid was recrystallized from cyclohexane-benzene to recover 5.0 g. (78 percent) of the desired compound. One additional recrystallization from cyclohexane-n-hexane gave the pure compound, m.p. 111°-112°C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]#[N:12].C(N(CC)CC)C.[CH2:20]([N:24]=[C:25]=[O:26])[CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:20]([NH:24][C:25](=[O:26])[NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]#[N:12])[CH2:21][CH2:22][CH3:23]
Reactant: N#Cc1c(N)sc2c1CCCC2
Reactant: CCCCN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)Nc1sc2c(c1C#N)CCCC2
Temperature: 80 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
A mixture of 5.35 g (30 mmol) of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (prepared according to Intermediate 1e), 2.0 ml (45 mmol) of triethylamine, 10 ml (90 mmol) of n-butyl isocyanate and 100 ml of toluene was stirred for 16 hours at 80° C. The solid formed was then isolated and was recrystallized from ethanol. Yield: 18%; mp.: 170°-171° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:19])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1>CN(C=O)C>[Cl:20][C:21]1[N:26]=[C:25]([N:16]2[CH2:17][CH2:18][CH:13]([C:10]3[CH:11]=[CH:12][C:7]([CH:5]([CH3:6])[C:4]([NH:3][CH2:1][CH3:2])=[O:19])=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)[CH:24]=[CH:23][N:22]=1
Reactant: CCNC(=O)C(C)c1ccc(C2CCNCC2)cc1
Reactant: Clc1ccnc(Cl)n1
Solvent: CN(C)C=O
Product: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
355 μL (2.53 mmol) TEA are added to a mixture of 600 mg (2.30 mmol) N-ethyl-2-(4-piperidin-4-yl-phenyl)-propionamide (VI.1) and 377 mg (2.53 mmol) 2,4-dichloro-pyrimidine in 25 mL DMF. The mixture is stirred for 3 h at rt. Subsequently the solvent is removed in vacuo and the residue is purified using reversed phase HPLC (water, 0.3% NH4OAc/acetone) to yield the desired product.
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][C@@H:28]6[CH2:32][CH2:31][CH2:30][O:29]6)[CH:22]=5)[C:17]4=[O:33])=[CH:12][C:11]=3[F:34])[CH2:6]2)[O:4]CC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[F:34][C:11]1[CH:12]=[C:13]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][C@@H:28]4[CH2:32][CH2:31][CH2:30][O:29]4)[CH:22]=3)[C:17]2=[O:33])[CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][C:5](=[O:4])[CH2:6]1
Reactant: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCN(c2ccc(N3CCc4cc(OC[C@@H]5CCCO5)ccc4C3=O)cc2F)C1
Temperature: 70 °C

Procedure:
A mixture of 2-[4-(1,4-dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluorophenyl]-6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-3,4-dihydro-2H-isoquinolin-1-one (8.4 g) and p-toluenesulfonic acid (3.4 g) in acetone/water (80 mL/40 mL) was heated for 12 h at 70° C. Then the acetone was removed in vacuum and the aqueous phase was neutralized with sodium hydrogencarbonate solution and then extracted several times with ethyl acetate. The organic phases were combined, dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 424.47 (C24H25FN2O4); MS (ESI): 425 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:29]=[CH:30][C:31]=4[CH3:32])[C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH:16]=3)[C:11]2=[O:33])=[CH:7][CH:6]=1.[CH3:36][NH2:37]>>[CH:26]1([NH:25][C:23](=[O:24])[C:22]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:20]([C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[C:11](=[O:33])[N:10]([CH2:9][C:8]3[CH:34]=[CH:35][C:5]([O:4][CH2:3][CH2:2][NH:37][CH3:36])=[CH:6][CH:7]=3)[CH:19]=[CH:18]4)[CH:21]=2)[CH2:28][CH2:27]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCCl)cc3)ccc2c1
Reactant: CN
Product: CNCCOc1ccc(Cn2ccc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc3c2=O)cc1

Procedure:
The title compound was prepared according to the method of Example 32 step (iii) using the product of Example 32 step (ii) and methylamine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1([CH2:21][OH:22])[CH2:19][CH2:18][CH:17]1[CH3:20].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1([CH:21]=[O:22])[CH2:19][CH2:18][CH:17]1[CH3:20]
Reactant: CC1CCC1(CO)c1cccs1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1CCC1(C=O)c1cccs1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (50 mL, 0.10 mmol) was added to CH2Cl2 (150 mL) at 23° C. and was cooled to −78° C. DMSO (16 g, 0.20 mmol) was added dropwise to the mixture and stirring was continued for 15 min. A solution of alcohol 4 (7.9 g, 0.041 mmol) in CH2Cl2 (50 mL) was then added dropwise, after which Et3N (44 g, 0.44 mmol) was added and the mixture was warmed to 23° C. After 1 h, the mixture was poured into saturated aqueous NaHCO3 and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic portions were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by FCC (silica gel, 100% hexane followed by 2:1 hexane/CH2Cl2) to afford the above named aldehyde 5.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18](O)=[O:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([NH:8][C:18](=[O:19])[CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN
Reactant: COc1ccccc1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)Cc1ccccc1OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Heptan-1-amine (1 g, 8.679 mmol was dissolved in DMF (10 ml), (2-methoxyphenyl)acetic acid (1.587 g, 9.547 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (3.065, 9.547 mmol) and N-ethyl-N,N-diisopropylamine (2.356 g, 18.226 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of NaHCO3 (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 2.00 g of N-heptyl-2-(2-methoxyphenyl)acetamide (yield 87.5%).
Reaction SMILES: C([N:4]([C@@H:12]1[CH2:21][CH2:20][CH2:19][C:18]2[N:17]=[CH:16][CH:15]=[N:14][C:13]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=O)C.O.NN>CO.CCOC(C)=O>[N:17]1[C:18]2[CH2:19][CH2:20][CH2:21][C@@H:12]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10])[C:13]=2[N:14]=[CH:15][CH:16]=1
Reactant: CC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CCCc2nccnc21
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCc2nccnc21
Yield: 94.9 %

Procedure:
A solution of (R)-tert-butyl acetyl(5,6,7,8-tetrahydroquinoxalin-5-yl)carbamate (293 mg) in methanol (10 mL) was treated with hydrazine hydrate (0.5 mL) for 1.5 h. The mixture was diluted with EtOAc and washed twice with saturated aqueous sodium chloride. The organic layer was separated, dried with sodium sulfate, and concentrated in vacuo to provide 238 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7]C(C)(C)C.[OH:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([OH:38])=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N([OH:62])N=NC=2C=1>ClC(Cl)C.O>[C:36]([C@@H:35]([C@H:34]([C:6]([OH:12])=[O:7])[OH:33])[OH:62])([OH:38])=[O:37].[OH:37][CH2:36][C:35]([CH3:40])([CH3:39])[C:34]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[N:23]=[CH:22][C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[CH2:14][N:2]([CH3:1])[C:3](=[O:13])[CH2:4][NH2:5])=[CH:26][N:25]=2)[CH2:32][CH2:31]1)=[O:33]
Reactant: CC(C)(CO)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CN(Cc1cccc(-c2cnc(N3CCN(C(=O)C(C)(C)CO)CC3)nc2)c1)C(=O)CN
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Temperature: 60 °C
Reaction time: 6 h
Yield: 33.5 %

Procedure:
tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (250 mg) was dissolved in dichloroethane (3 ml), and 3-hydroxy-2,2-dimethylpropionic acid (74 mg), WSC hydrochloride (131 mg), and HOBt (92 mg) were added thereto, followed by stirring at 60° C. for 6 hours. To the reaction mixture was added water, followed by extraction with CHCl3. After drying over Na2SO4, the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The product was dissolved in EtOH (3 ml), and 4 M hydrogen chloride/EtOAc (1 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The product was dissolved in EtOH (3 ml), and L-tartaric acid (27 mg) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain N-(3-{2-[4-(3-hydroxy-2,2-dimethylpropanoyl)piperazin-1-yl]pyrimidin-5-yl}benzyl)-N-methylglycinamide L-tartrate (62 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)=[O:4].[CH2:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:24]1([CH2:23][N:30]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)=[O:4])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C(CBr)c1cccc(OCCCOCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(CN(Cc1ccccc1)Cc1ccccc1)c1cccc(OCCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-bromo-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanone (13.17 g), dibenzylamine (6.4 g) and dichloromethane (25 mL) was added a solution of sodium carbonate (7.6 g) in water (50 mL). The reaction mixture was stirred at ambient temperature overnight. The organic layer was separated and concentrated to a minimum and tert-butyl methyl ether was added. The organic layer was washed with dilute acetic acid (4 times) and 0.1N sodium hydroxide once and brine once. The organic solution was concentrated to dryness. The oil was washed with methanol and purified by chromatography to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29]CC2C=CC=CC=2)=[CH:25][C:24]=1[O:37][CH3:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])(C)C.[H][H].[CH2:42](O)[CH3:43]>[Pd]>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=1[O:37][CH3:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][CH2:42][CH3:43]
Reactant: CCO
Reactant: [H][H]
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(OCc2ccccc2)cc1OC
Agent: [Pd]
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1CCCC)c1ccc(O)cc1OC

Procedure:
A solution of 2.46 g (4.64 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(4-benzyloxy-2-methoxyphenyl)octanamide (prepared as described in Example 123) in 100 ml of ethanol was vigorously stirred at 40° C. under a stream of hydrogen in the presence of 10% palladium-on-charcoal for 1.5 hours. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid to remove the catalyst, and the filtrate was concentrated to dryness by evaporation under reduced pressure. The residue was purified by column chromatography through 100 g of silica gel using a 49:1 by volume mixture of ethyl acetate and methanol as the eluent, to give a crude product containing the title compound. This product was further purified by column chromatography through silica gel under the same conditions as above to give 1.62 g (yield 79%) of the title compound as a foam-like substance.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3Cl)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9].[CH:38]1[C:50]2[CH:49]([CH2:51][NH2:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1>C(#N)C>[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3[NH:52][CH2:51][CH:49]2[C:50]3[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=3[C:43]3[C:48]2=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCC1c2ccccc2-c2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC4c5ccccc5-c5ccccc54)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
Triethylamine (0.38 ml, 2.7 mmol) was added to a stirred solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (1.0 g, 2.3 mmol) (Preparation 45) and 9H-fluoren-9-ylmethanamine (0.49 g, 2.5 mmol) (J. Org. Chem., 1971, 36(23), 3539) in acetonitrile (30 ml) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was partially redissoved in ethyl acetate (30 ml). The ethyl acetate was washed with water (1 ml) and a saturated aqueous sodium chloride solution (10 ml). The organic phase was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate (96:4 by volume) increasing in polarity to dichloromethane: ethyl acetate (94:6 by volume). The solvent was removed under reduced pressure to give the title compound (1.23 g) as a foam.