Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(F)=C(C=CC=1)CNC([C@@H]1C[C@]2(CO)[C@@H](C2)N1C(=O)[CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]1)=O.C(O[C:41]([N:43]1[CH2:47][C@@:46]([F:49])([CH3:48])[CH2:45][C@H:44]1[C:50](=[O:63])[NH:51][C@@H:52]([C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[C:56]=1[F:62])[CH2:53][OH:54])=[O:42])(C)(C)C.ClCl.CCOC(C)=O>>[Cl:61][C:57]1[C:56]([F:62])=[C:55]([C@H:52]([NH:51][C:50]([C@@H:44]2[CH2:45][C@:46]([F:49])([CH3:48])[CH2:47][N:43]2[C:41](=[O:42])[CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]2)=[O:63])[CH2:53][OH:54])[CH:60]=[CH:59][CH:58]=1
Reactant: CC(=O)c1cn(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)c2ncccc12
Reactant: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Agent: ClCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(CC(=O)N2C[C@](C)(F)C[C@H]2C(=O)N[C@H](CO)c2cccc(Cl)c2F)c2ncccc12

Procedure:
The title compound was prepared in 2 steps according to the procedure described for the preparation of Example 610 (1R,3S,5S)-2-[2-(3-acetyl-pyrrolo[2,3-b]pyridin-1-yl)-acetyl]-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide from (2S,4R)-2-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-4-fluoro-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared using similar protocols as described in Scheme B9). White powder. TLC, Rf (CH2/Cl2/EtOAc 9:1)=0.60; MS (UPLC/MS): 519.3/521.3 [M+H]+, 563.3/565.3 [M+HCOO]−; tR (HPLC conditions a): 2.96 min.
Reaction SMILES: [C:1]12([C:8]3[C:13](Cl)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:24][N:25]1[C:29]([CH2:30][OH:31])=[N:28][CH:27]=[N:26]1.[H-].[Na+].O>CN(C)C=O>[C:1]12([C:8]3[C:13]([O:31][CH2:30][C:29]4[N:25]([CH3:24])[N:26]=[CH:27][N:28]=4)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-(bicyclo[2.2.1]hept-1-yl)-6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (0.125 g, 0.39 mM) and (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.08 g, 0.47 mM; prepared using the conditions described in EP-A-421210) in N,N-dimethylformamide (20 ml) was added sodium hydride (0.015 g of a 60% dispersion in oil, 0.47 mM eq) and the reaction mixture was stirred at room temperature for 3 hours. Water was added until the solution became cloudy and after stirring for a further 15 minutes a solid was collected by filtration. This solid was recrystallised from ethyl acetate-dichloromethane to give the required product (0.048 g, m.p.=244-246° C.). 1H NMR (360 MHz, DMSO) δ1.39 (2H, m), 1.67-1.84 (8H, m), 2.30 (1H, m), 3.93 (3H, s), 5.70 (2H, s), 7.52-7.62 (3H, m), 8.00 (1H, s), 8.35 (1H, s), 8.38 (2H, m); (Regiochemistry was established using nOe data). MS (ES+) m/e 402 [MH]+. Anal. Found C, 65.71; H, 5.65; N, 24.07. C22H23N7O requires C, 65.82; H, 5.77; N, 24.42%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([O:14][CH2:15]C)=[O:13])=[C:4]([N:7](C)[C:8]([NH2:10])=O)[S:5][CH:6]=1.[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:17][N:10]=[C:8]=[N:7][C:4]1[S:5][CH:6]=[C:2]([CH3:1])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1c(C)csc1N(C)C(N)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN=C=Nc1scc(C)c1C(=O)OC

Procedure:
A stirred solution of ethyl 4-methyl-2-(N1 -methylureido)-thiophene-3-carboxylate (2,3 g), triphenylphosphine (2,62 g), triethylamine (1.4 ml) and carbontetrachloride (5 ml) in CH2Cl2 (50 ml) was refluxed for 30 min, whereafter it was evaporated in vacuo. The oily residue was extracted twice with boiling petrol ether. The combined petrol ether solutions were evaporated to give N-methyl N'-(3-carbomethoxy-4-methyl-thien-2-yl)-carbodiimide as an oil. The presence of the carbodiimide moeity was confirmed by an IR absorbtion band at 2140 cm-1.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(N(CC)CCNCC)C>O1CCCC1.CCCCCC.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:15]([CH2:16][CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCCOCc1ccccc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCNCCN(CC)CC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CC(CCCOCc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1

Procedure:
A solution of (R)-4-benzyl-3-(5-benzyloxypentanoyl)oxazolidin-2-one (132 g) in tetrahydrofuran (660 mL) was added dropwise to a mixture of sodium hexamethyldisilazane (1.9 M in tetrahydrofuran) (702 mL) and tetrahydrofuran (660 mL) at −78° C. The reaction temperature was rose to −40° C. To the mixture was added dropwise tert-butyl bromoacetate (85 mL) at −78° C. The reaction temperature was rose to −36° C. To the mixture was added dropwise N,N,N′-triethylethylenediamine (33 mL) at ice temperature. And then, to the mixture were added water (530 mL) and hexane (660 mL). The aqueous layer was removed, and the organic layer was washed with aqueous 20 w/v % citric acid (660 mL×3), water (660 mL), saturated aqueous sodium bicarbonate (660 mL) and brine (660 mL), then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (196 g) as a crude product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.Cl.[CH3:32][N:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:33]([CH3:40])[CH3:32])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: CN(C)CCCC(=O)O
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.8 %

Procedure:
To a stirred DCM (15 mL) solution of the product from Example 1 (58 mg), 4-(dimethylamino)butyric acid hydrochloride (28.2 mg) and TEA (0.059 mL) was added HATU, (58.7 mg) under nitrogen. The resulting solution was stirred at rt for 16 h. The solvent was evaporated and the residue was taken up in MeOH and the crude product purified by RPHPLC to afford the title compound 5 mg.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](O)=[O:9])=[CH:3][CH:2]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([N:19]([O:20][CH3:21])[CH3:18])=[O:9])=[CH:3][CH:2]=1
Reactant: CNOC
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A mixture of 2-(biphenyl-4-yl)acetic acid (1 g, 4.7 mmol), N,O-dimethylhydroxylamine hydrochloride (458 mg, 4.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (900 g, 4.7 mmol), hydroxybenzotriazole (635 mg, 4.7 mmol), and triethylamine (1.42 g, 14.1 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. When TLC indicated that 2-(biphenyl-4-yl)acetic acid was consumed, the reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=8:1) to afford 2-(biphenyl-4-yl)-N-methoxy-N-methylacetamide (1.0 g, yield 83%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([C:11](=[O:24])[CH2:12][NH:13][C:14](=O)[C:15]2[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH3:22])[CH:16]=2)[CH:8]=[C:7]([CH3:25])[N:6]=1)[CH:2]([CH3:4])[CH3:3].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH2:1]([C:5]1[CH:10]=[C:9]([C:11]2[O:24][C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH3:22])[CH:16]=3)=[N:13][CH:12]=2)[CH:8]=[C:7]([CH3:25])[N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(C(=O)NCC(=O)c2cc(C)nc(CC(C)C)c2)cc(C)n1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Cc1cc(-c2ncc(-c3cc(C)nc(CC(C)C)c3)o2)cc(C)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a solution of N-[2-(2-isobutyl-6-methyl-pyridin-4-yl)-2-oxo-ethyl]-2,6-dimethyl-isonicotinamide (9 mg, 27 μmol) in THF (1 mL), Burgess reagent (20 mg, 80 μmol) is added. The mixture is stirred at 60° C. for 2 h before it is concentrated. The crude product is purified on prep. TLC plates with DCM containing 5% of methanol to give 2-isobutyl-4-[2-(2,6-dimethyl-4-pyridinyl)-oxazol-5-yl]-6-methyl-pyridine (5 mg) as a pale yellow wax; LC-MS: tR=0.96*, [M+1]+=322.12; 1H NMR (CDCl3): δ 1.00 (d, J=6.8 Hz, 6H), 2.13-2.24 (m, 1H), 2.64 (s, 3H), 2.66 (s, 6H), 2.72 (d, J=7.3 Hz, 2H), 7.24 (s, 1H), 7.31 (s, 1H), 7.67 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Si](C)(C)C)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)(C)CCCCC#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CCCCCC(C)(C)c1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
[7-(3,5-Dimethoxyphenyl)-7-methyl-1-octynyl]trimethylsilane (1 equiv.) was dissolved in anhydrous methanol (0.8 M), anhydrous potassium carbonate (0.2 equiv.) was added and the heterogeneous mixture was stirred at room temperature, under argon, for 24 hours. The reaction mixture was diluted with water and extracted with diethyl ether. The ether extract was dried, concentrated by rotary evaporation and the residue was purified by chromatography on silica gel (5% diethyl ether-petroleum ether) to give the title compound in 76% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16].S(=O)(=O)([OH:19])N.[O-]Cl=O.[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([OH:19])=[O:8])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: NS(=O)(=O)O
Reactant: COCCCCc1cc(C=O)ccc1OC
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: COCCCCc1cc(C(=O)O)ccc1OC
Reaction time: 3 h

Procedure:
To a stirred suspension of 4-methoxy-3-(4-methoxy-butyl)-benzaldehyde (300 mg, 1.35 mmol) and sulfamic acid (176 mg, 1.81 mmol) in 80% acetic acid (2.3 mL) is added dropwise a solution of 80% NaClO2 (127 mg, 1.40 mmol; dissolved in 170 μL of H2O) in water (0.65 mL) over 5 min and by keeping the temperature at 18-20° C. Stirring of the yellow slurry is continued over 3 hrs at 20° C. before adding another aliquot of 80% NaClO2 (151 mg, 1.67 mmol; dissolved in 205 μL of H2O), dissolved in water (0.8 mL), and sulfamic acid (130 mg, 1.34 mmol) in 80% aqueous acetic acid. After stirring overnight, the reaction mixture is diluted by adding water (2.3 mL), the resulting suspension is stirred for 30 min and filtered. The precipitate is dried to give the title product as white solid. TLC, Rf (CH2Cl2/MeOH 98:2)=0.5. MS: 239.0 [M+H]+. 1H-NMR (CD3OD): δ 1.55-1.7 (m, 4H), 2.65 (t, 2H), 3.31 (s, 3H), 3.41 (t, 2H), 3.89 (s, 3H), 4.87 (s, 1H+D2O), 6.98 (m, 1H), 7.78 (s, 1H), 7.87 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:25]=[C:26]([NH:30][C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=4[F:11])[CH:27]=[CH:28][CH:29]=3)=[O:23])=[CH:20][N:19]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Solvent: c1ccncc1
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)c3c(F)cccc3F)c1)cn2C1CCCC1
Temperature: 120 °C
Yield: 48.4 %

Procedure:
2,6-difluorobenzoyl chloride (82.1 mg, 0.47 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone (100 mg, 0.31 mol) in pyridine (3 mL). The resulting solution was heated to 120° C. for 1 h at this time the reaction was quenched with water and concentrated. The residue was dissolved in EtOAc and washed with 1N NaOH and water. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 97:3) afforded the title compound as a white solid (105 mg, 73%). MS: 462.2 (MH+); HPLC Rf: 5.70 min. (HPLC method 4).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[N:27][CH:28]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]([CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)[C:5](=[O:7])[CH3:6])=[N:27][CH:28]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc(NCCN4CCCC4)nc3)nc2)cc1
Solvent: ClCCl
Product: CC(=O)N(CCN1CCCC1)c1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
45 μL (0.48 mmol) acetic anhydride is added to a solution of 89 mg (0.22 mmol) {5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-pyrrolidin-1-yl-ethyl)-amine in 2 mL DCM. The reaction solution is stirred for 16 h at RT. The solvent is eliminated i.vac. and further purification is carried out by HPLC-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:27]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:27][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:15])[F:16])[O:11][N:10]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CC(c2ccc(CBr)c(Cl)c2)=NO1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 26.2 g of 3-(3-chloro-4-methylphenyl)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 200 mL of 1,2-dichloroethane, 12.1 g of N-bromosuccinimide and 0.81 g of α,α′-azobisisobutyronitrile were added and the resultant reaction mixture was stirred at 80° C. for 3 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and was washed with water (70 mL×2). Subsequently, the washed reaction mixture was dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure to obtain 34.1 g of a crude objective substance as a brown oily substance. This substance was used in the next process as it was without being further purified.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[CH2:23][CH:24]=[CH2:25]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH:14][CH2:25][CH:24]=[CH2:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Product: C=CCNC[C@H](NC(=O)OCc1ccccc1)C(=O)OC

Procedure:
The β-amino functionality of Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine, methyl ester is then allylated with allyl trichloroacetimidate to give the corresponding Nα -(benzyloxycarbonyl)-β-(allylamino)-L-alanine, methyl ester using conditions described previously in Scheme D, step b.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([OH:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.F[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][CH2:3][C:4]1[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([O:14][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COCc1cc2ccccc2c(O)c1-c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCc1cc2ccccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 30 %

Procedure:
3-[(Methyloxy)methyl]-2-phenyl-1-naphthalenol (145) (46 mg, 0.17 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMF at 100° C. to give 20 mg (30%) of the title compound (146) as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 3.34 (s, 3H), 4.32 (s, 2H), 6.71 (d, J=8.8 Hz, 2H), 7.16-7.20 (m, 2H), 7.20-7.30 (m, 3H), 7.45 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.4 Hz, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.4 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.98 (s, 1H), 9.79 (s, 1H). LCMS (APCI): m/z 369 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].[CH:24]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[CH:24]1([CH2:30][O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a mixture of ethyl 4-hydroxy-3-nitrobenzoate (2-1) (2.11g, 10.0 mmol), cesium carbonate (6.52 g, 20.0 mmol), and sodium iodide (0.15g, 1.0 mmol) in DMF (20 ml) under nitrogen was added cyclohexylmethylbromide (1.67 ml, 12.0 mmol). The mixture was stirred 48 h at 60° C. The resulting mixture was evaporated under reduced pressure. To the residue was added water (100 ml), and the aqueous mixture was extracted with methylene chloride (2×200 ml). The organic fraction was washed with saturated sodium carbonate solution (100 ml) and brine (100 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was crystallized from ether/hexane to give product 21-2 as yellow crystals, mp: 79°-80° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:45])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33][CH2:32]1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:45])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:32][CH2:33][C@H:34]([NH2:37])[CH2:35][CH2:36]1)(=[O:3])[CH3:2]
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](NC(=O)OC(C)(C)C)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](N)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(2R,3R,4R,5R)-2-(2-Chloro-6-{[trans-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclohexyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydrofuran-3,4-diyl diacetate (Intermediate 1) (12.49 g), was dissolved in trifluoroacetic acid—dichloromethane mixture (50:50; 40 ml). The mixture was stirred at room temperature for 1-2 h and then evaporated down in vacuo. The residue was partitioned between ethyl acetate and 2N aq.sodium bicarbonate solution, making sure the trifluoroacetic acid was neutralised. The organic phase was separated, washed with brine, dried (MgSO4), and evaporated down in vacuo, to give the title compound, 11.2 g.
Reaction SMILES: [CH:1]([C:4]1[C:12]([O:13]C2CCCCO2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2C1CCCCO1)([CH3:3])[CH3:2].C(C1C(O)=CC=C2C=1C=NN2C1CCCCO1)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: CC(C)c1c(O)ccc2c1cnn2C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1c(O)ccc2[nH]ncc12
Temperature: 25 °C
Yield: 280.2 %

Procedure:
A mixture of 4-isopropyl-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (301 mg, 0.871 mmol) and 4-isopropyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol (586 mg, 2.25 mmol) was made into a solution of the mixture in dichloromethane (26 ml), followed by adding thereto trifluoroacetic acid (6.5 ml), and the resulting mixture was stirred for 4 hours while being maintained at room temperature. The reaction solution was diluted with ethyl acetate, neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate, and the extract solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain 4-isopropyl-1H-indazol-5-ol (430 mg, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[CH2:8][CH2:7][C:6](Cl)([Cl:13])[CH:5](Cl)[C:4]=2[C:3]=1[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>COCCOCCOC.[Zn]>[Cl:12][C:10]1[C:9]2[CH2:8][CH2:7][C:6]([Cl:13])=[CH:5][C:4]=2[C:3]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:2]([CH3:1])[CH:11]=1
Reactant: CCOC(=O)CCc1c(C)cc(Cl)c2c1C(Cl)C(Cl)(Cl)CC2
Agent: [Zn]
Solvent: COCCOCCOC
Product: CCOC(=O)CCc1c(C)cc(Cl)c2c1C=C(Cl)CC2
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
Activated zinc dust (0.55 g., 8.43 mmoles) was added to a solution of ethyl 3-(2-methyl-5,6,7,8-tetrahydro-4,7,7,8-tetrachloronaphthalen-1-yl)propanoate in dry diglyme (2.5 ml) and heated and stirred in an oil bath rapidly (10 minutes) to about 140° C. at which time the reaction proceeded vigorously and exothermically and refluxed. The reflux subsided in about 1 minute. Heating with an oil bath at 140°-150° C. was continued for 15 minutes Tlc (silica-CH2Cl2) showed reaction complete. The reaction was cooled to room temperature and partitioned between ether (150 ml) and 1N HCl (25 ml). Extract ether successively with 1N HCl, water four times, saturated solution of NaHCl3 ; dried, (MgSO4), filtered and the solvents evaporated to leave 1.99 g of title compound as a gum. Rf =0.61 (silica-CH2Cl2).