Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH3:21]>CS(C)=O>[CH2:17]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 70 °C
Yield: 94.9 %

Procedure:
To a stirred solution of 4-(4-bromophenyl)phenol (25.5 g, 0.102 mol) in 400 mL of dimethylsulfoxide was added 2.5N NaOH (40.9 ml, 0.102 mol) followed by n-pentyl bromide (12.7 mL, 0.102 mol). The resulting mixture was heated at 70° C. for a period of 18 h. After cooling, the yellow solution was partitioned between ethyl acetate (1000 ml) and water (500 ml). The organic phase was washed with water (3×) and brine and dried with magnesium sulfate. The solvent was removed in vacuo to give 4-(4-n-pentoxyphenyl)bromobenzene (30.9 g): 1H NMR (400 MHz, DMSO-d6) δ 0.93 (t, 3, J=7.2 Hz), 1.41 (m, 4), 1.79 (m, 2), 3.97 (t, 2, J=6.6 Hz), 6.94 (d, 2, J=8.8 Hz), 7.39 (d, 2, J=8.6 Hz), 7.45 (d, 2, J=8.8 Hz), 7.51 (d, 2, J=8.6 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([F:9])[CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:23])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11].Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:9][CH:6]1[CH2:5][N:4]([C:10]([C:12]2[N:13]=[C:14]([CH3:23])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])[CH:3]([CH2:2][NH:1][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:8][CH2:7]1
Reactant: Cc1nc(C(=O)N2CC(F)CCC2CN)c(-c2ccccc2)s1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CC(F)CCC2CNc2ccc(C(F)(F)F)cn2)c(-c2ccccc2)s1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (2-(aminomethyl)-5-fluoropiperidin-1-yl)(2-methyl-5-phenylthiazol-4-yl)methanone (0.18 mmol, 0.06 g), 2-chloro-5-(trifluoromethyl)pyridine (0.38 mmol, 0.07 g) and Cs2CO3 in DMF (1.5 mL) was stirred at 120° C. overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The desired (5-fluoro-2-((5-(trifluoromethyl)pyridin-2-ylamino)methyl)piperidin-1-yl)(2-methyl-5-phenylthiazol-4-yl)methanone was isolated by preparative HPLC. MS (ESI) 479 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[O:18][C:17]([CH3:19])=[N:16][C:15]=3[CH3:20])=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.[Li][CH3:35]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[O:18][C:17]([CH3:19])=[N:16][C:15]=3[CH3:20])([OH:13])[CH3:35])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(=O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: COc1nc2ccc(C(C)(O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -78 °C

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,4-dimethyloxazol-5-yl)methanone (0.225 g, 0.474 mmol, Intermediate 11: step b) was added THF (15 mL). The solution was cooled to −78° C. and MeLi (1.6 M in Et2O, 0.36 mL, 0.58 mmol) was introduced which resulted in an immediate light orange homogeneous mixture. After 35 minutes the reaction mixture was quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (4×30 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (10% CH3CN-DCM increasing to 25% CH3CN and then to 5% MeOH) provided the title compound as a pale yellow amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.26 (d, J=1.9 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.61 (dd, J=8.7, 2.1 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.35 (s, 2H), 4.07 (s, 3H), 2.57 (s, 1H), 2.39 (s, 3H), 1.99 (s, 3H), 1.92 (s, 3H); MS (ESI): mass calcd. for C25H22ClF3N2O3, 490.1, m/z found 491.1 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(2,4-dimethyloxazol-5-yl)ethanol was purified by chiral chromatography (Chiralpak AD-H, solvent: 95% heptane/5% ethanol), to give 2 enantiomers. The first eluting enantiomer was Example 10b and the second eluting enantiomer was Example 10c.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:16]([CH2:20][CH:21]2[CH2:24][C:23](=[O:25])[CH2:22]2)[C:17]([OH:19])=[O:18])[CH:11]=[CH:12][C:13]=1[S:14][CH3:15].[Mn]([O-])(=O)(=O)=[O:27].[K+].[OH2:32]>CO>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:16]([CH2:20][CH:21]2[CH2:22][C:23](=[O:25])[CH2:24]2)[C:17]([OH:19])=[O:18])[CH:11]=[CH:12][C:13]=1[S:14]([CH3:15])(=[O:27])=[O:32]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CSc1ccc([C@@H](CC2CC(=O)C2)C(=O)O)cc1Cl
Reactant: O
Agent: [K+]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CC(=O)C2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 27 %

Procedure:
In a round bottom flask was placed sodium periodate (0.29 g, 1.36 mmol) in water (1.0 ml). To this was added a solution of 2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-(3-oxo-cyclobutyl)-propionic acid (prepared as in Example 93, 0.22 g, 0.74 mmol) in methanol (3 ml) and the reaction was stirred at 25° C. for 6 h. After this time, the solids were filtered off and the filtrate was concentrated in vacuo and azeotroped with acetonitrile (2×10 ml). The resulted in an off-white solid that was then dissolved in methanol (4 ml) and to this was added potassium permanganate (0.17 g, 1.07 mmol) in water (2 ml) and stirred at 25° C. for 5 h. After this time, there was still starting material present by HPLC so another portion of potassium permanganate (80 mg, 0.51 mmol) in water (1 ml) and it was stirred overnight. The reaction still showed starting material was not consumed but it was worked up anyway. The reaction was filtered through celite and washed with a solution of methanol/methylene chloride (1:1). The organics were concentrated in vacuo and azeotroped with acetonitrile (3×10 ml). Purification on an AnaLogix Intelliflash system (40 g column, 3% methanol/methylene chloride+1% acetic acid) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionic acid (65 mg, 27%) as a white gummy solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.93-2.32 (m, 3H, CH and CH2), 2.63-2.80 (m, 2H, 2×CH or 2×CH2), 2.90-3.13 (m, 2H, 2×CH or 2×CH2), 3.35 (s, 3H, SO2CH3), 3.72 (t, J=7.6 Hz, 1H, ArCHCO2), 7.58 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 7.72 (d, Jm=1.6 Hz, 1H, Ar), 8.02 (d, Jo=8.2 Hz, 1 H, Ar), 12.81 (brs, 1H, CO2H).
Reaction SMILES: [NH2:1][C:2]([CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])([CH3:4])[CH3:3].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][C:24](O)=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.O1CCCC1CCO>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][C:24]([NH:1][C:2]([CH3:4])([CH3:3])[CH:5]([OH:6])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: CC(C)(N)C(O)c1ccccc1
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: OCCC1CCCO1
Product: COc1ccc(CC(=O)NC(C)(C)C(O)c2ccccc2)cc1OC
Reaction time: 20 h
Yield: 82 %

Procedure:
A solution of 8.3 g. (0.05 mole) of α-(1-amino-1-methylethyl)benzenemethanol, 9.8 g. (0.05 mole) of 3,4-dimethoxyphenylacetic acid and 13.6 g. (0.055 mole) of EEDQ (Aldrich Chem. Co.) in 300 ml. of tetrahydrofuran-ethanol is refluxed for 45 minutes and then allowed to stand for 20 hours at 25° C. The solution is evaporated in vacuo. The residue is taken up with 250 ml. of ethyl acetate, washed with dilute HCl, followed by washing with aqueous NaHCO3. Subsequently, the extract is washed with aqueous NaCl, dried (Na2SO4) and evaporated to dryness in vacuo. Crystallization of the residue from ether gives 14.0 g. (82% yield) of pure 2-(3,4-dimethoxyphenyl)-N-(β-hydroxy-α,α-dimethylphenethyl)acetamide, m.p. 123°-124° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[C:18]([CH2:29][OH:30])=[CH:17][N:16]=1>CO.C(Cl)Cl>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:19]1[C:18]([CH2:29][OH:30])=[CH:17][N:16]=[C:15]([NH:14][CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[N:20]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCNc1ncc(CO)c(-c2ccc(Cl)cc2Cl)n1
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(CO)c(-c3ccc(Cl)cc3Cl)n2)nc1
Yield: 51 %

Procedure:
The process of Example 140 is repeated using 2-chloro-5-nitro-pyridine and {2-[(2-aminoethyl)amino]-4-(2,4-dichlorophenyl)pyrimidin-5-yl}methan-1-ol. Chromatography of the residue (silica gel, 5% methanol/methylene chloride) afforded 200 mg (51%) of [4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]methan-1-ol as a yellow solid.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]CC)=O)[CH2:10][CH2:9]1.[NH2:26][NH2:27]>C(O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:26][NH2:27])=[O:17])[CH2:10][CH2:9]1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccccc2-c2ccccc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{12} (4.34 g, 13.4 mmol, 1 equiv.), anhydrous hydrazine (1.3 mL, 40.1 mmol, 3 equiv.), ethanol (27.0 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{12} (4.02 g, 93%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 8.12 (br s, 1H), 7.50 (dd, 1H, J=2.0, 7.0 Hz), 7.41-7.34 (m, 5H) 7.33-7.29 (m, 2H), 7.26-7.24 (m, 1H), 3.83 (br s, 2H), 3.40 (s, 2H), 3.04 (s, 2H), 2.47 (br s, 4H), 2.36 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.4, 142.6, 141.3, 135.3, 130.0, 129.8, 129.4, 127.8, 127.0, 126.8, 60.5, 59.5, 53.7, 52.7.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][C:16]1[CH:17]=[CH:18]C(C)=[N+:20]([O-])[CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:5]([O:4][CH2:1][C:2]1[CH:18]=[CH:17][C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:21][N:20]=1)(=[O:7])[CH3:6]
Reactant: Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccc(OCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 80 ml. of acetic anhydride stirred at 135°C. is added slowly 39.8 g. (0.185 mol) of the above N-oxide. The solution is stirred at this temperature for 30 minutes and then poured into 500 ml. of ice-water. After stirring the mixture for two hours it is extracted with a mixture of ethyl acetate and ether. The extract is washed with water, dried and evaporated to dryness. The residue is passed through an alumina column with ether as the eluent. Evaporation of the first fraction yields 2-acetoxymethyl-5-benzyloxypyridine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([Br:10])[CH:3]=1.FC(F)(F)C(O)=O.[N-:18]=[N+:19]=[N-:20].[Na+].[C:22](O)(=O)C>C(OC(OCC)OCC)C>[Br:10][C:4]1[CH:3]=[C:2]([N:1]2[CH:22]=[N:20][N:19]=[N:18]2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(N)cc1Br
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: COc1ccc(-n2cnnn2)cc1Br
Yield: 67 %

Procedure:
4-Amino-2-bromoanisole (Desc. 4(a); 4.7 g) was dissolved in triethylorthoformate (50 ml), trifluoroacetic acid (1.8 ml) was added and the mixture heated at reflux for 48 hours. The solvent was removed in vacuo to afford a brown solid. Sodium azide (2.25 g) and acetic acid (25 ml) were added and the mixture heated at reflux for 6 hours. The product was purified on flash silica eluting with dichloromethane containing increasing proportions of methanol (0.25%, 0.5 and 0.75%) to give the title compound as a brown solid (3.98 g, 67% yield); δH (250MHz, DMSO-d6) 4.07 (3H, s, ArOCH3), 7.50 (1H, d, J 9Hz, 6-H), 8.03 (1H, dd, J 3, 9Hz, 5-H), 8.32 (1H, d, J 3Hz, 3-H), 10.16 (1H, s, 5'-H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:13].O1CCOCC1.CCN(C(C)C)C(C)C.[CH2:29]([SH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:29]([S:36][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:13])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Fc1cc2c(Cl)ccnc2cc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2c(Cl)ccnc2cc1SCc1ccccc1
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A vial was charged with 7-bromo-4-chloro-6-fluoroquinoline (0.141 g, 0.541 mmol), Xantphos (0.016 g, 0.027 mmol), and Pd2(dba)3 (0.012 g, 0.014 mmol) and after flushing with argon, dioxane (1.083 ml) and n,n-diisopropylethylamine (0.189 ml, 1.083 mmol) were added in sequence. The vial was sealed, and was placed in a heating bath at 80° C. for 10 minutes, after which benzylmercaptan (0.067 ml, 0.568 mmol) was added drop wise via syringe. The reaction was stirred for 30 minutes. The material was diluted with water, and washed with DCM (×3), and the combined organics were dried via phase separator and concentrated in vacuo. The material was purified via silica gel chromatography eluting with 0-50% ethyl acetate in heptane to yield 7-(benzylthio)-4-chloro-6-fluoroquinoline (0.148 g, 0.487 mmol, 90% yield) as a light yellow solid. m/z (ESI) 304.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32]C(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[C:50]1([CH:56]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH2:57]NC2N=C(NN)N=C3C=2N=CN3[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH2:57][CH:56]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NN)nc32)[C@H](O)[C@@H]1O
Product: CCOC(=O)c1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
This compound is prepared analogously to 1-[6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 168 step 3) by replacing N-[(1S,2R,3S,4R)-4-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-hydrazino-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide with N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-hydrazino-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide.
Reaction SMILES: C([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([Br:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:19]C(=O)C(C)(C)C)[C@H:6]([O:26][CH2:27][CH2:28][O:29][CH3:30])[C@H:5]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.[OH-].[K+].O.NN>CO>[Br:17][C:16]1[N:11]2[CH:10]=[CH:9][C:8]3[C@@H:7]([OH:19])[C@H:6]([O:26][CH2:27][CH2:28][O:29][CH3:30])[C@@H:5]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:4][C:13]=3[C:12]2=[N:14][C:15]=1[CH3:18]
Reactant: COCCO[C@H]1[C@H](OC(=O)C(C)(C)C)c2ccn3c(Br)c(C)nc3c2N(C(C)=O)[C@@H]1c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCO[C@H]1[C@H](O)c2ccn3c(Br)c(C)nc3c2N[C@@H]1c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A suspension of 0.30 g (0.54 mmol) of (7R,8R,9R)-10-acetyl-3-bromo-8-(2-methoxyethoxy)-2-methyl-9-phenyl-7-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine, 0.10 ml (0.60 mmol) aqueous potassium hydroxide (6 N) and 0.20 ml (5.14 mmol) hydrazine hydrate in methanol is stirred al 60° C. for 4 h. The methanol is removed in vacuo and the reaction mixture is diluted with water. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (toluene/dioxane/acetic acid: 8/1/1) to give 0.12 g (0.28 mmol/52%) of the title compound as an amorphous solid. 1H-NMR (200 MHz, [D6] DMSO): δ=2.30 (s, 1H), 3.09 (s, 1H), 3.10-3.30 (m, 2H), 3.45-3.70 (m, 2H), 4.48 (d, 1H), 4.68 (d, 1H), 6.96 (d, 1H), 7.20-7.51 (m, 5H), 7.58 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=2[C:5]([F:19])=[C:4](F)[N:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].CC(O)C.CN1CCOCC1>O>[C:31]([O:30][C:29]([NH:28][C@@H:23]1[C@H:22]([NH:21][C:4]2[N:3]=[C:2]([Cl:1])[C:7]3[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=3[C:5]=2[F:19])[CH2:27][CH2:26][O:25][CH2:24]1)=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: CC(C)(C)OC(=O)N1Cc2c(F)c(F)nc(Cl)c2C1=O
Solvent: CC(C)O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To a mixture of tert-butyl 4-chloro-6,7-difluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (42.5 g, 139 mmol) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (36.2 g, 167 mmol) was added IPA (425 mL) followed by 4-methylmorpholine (18.40 mL, 167 mmol). The reaction mixture was stirred at 60° C. for 20 hours under a nitrogen atmosphere. HPLC analysis indicated that the reaction was complete. The reaction mixture was subsequently cooled to room temperature and water (890 mL) was added slowly. The suspension was cooled in an ice/water bath to 6° C. and was stirred for 1 hour. The solids were collected by filtration and washed with water (30 mL) used to rinse the reaction vessel. The filter cake was washed with additional water (350 mL) and allowed to dry on the filter. The filter cake was subsequently dried in a vacuum oven at 60° C. over the weekend to afford the title compound (64.78 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9H), 1.50 (s, 9H), 1.59-1.61 (m, 1H), 1.97-1.99 (m, 1H), 1.97-1.99 (m, 1H), 3.46-3.49 (m, 2H), 3.80-3.83 (m, 3H), 4.31-4.33 (m, 1H), 4.73 (s, 1H), 6.59 (d, J=7.30 Hz, 1H), 7.43 (d, J=7.30 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C22H30ClFN4O6, 501. found, 501.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.O1CCCC1.[CH3:25][NH2:26]>[Ti](Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:26][CH3:25])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: CN
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1

Procedure:
A solution of 63.2 g. (0.2 mol) of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one in 1.7 l. of tetrahydrofuran and 400 ml. of benzene was saturated with methylamine. A solution of 45.5 g. of titanium tetrachloride in 400 ml. of benzene was added slowly with ice cooling. After addition was complete, the reaction mixture was stirred and refluxed for 2 hours. It was then partitioned between water and methylene chloride. The organic layer was dried over sodium sulfate and evaporated. Crystallization from methylene chloride/hexane yielded 7-bromo-2-methylamino-5-(2-pyridyl)-3H-1,4-benzodiazepine, having a melting point of 208°-214°.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:34]#[N:35])=[CH:20][N:21]2[C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([OH:33])[CH:25]=2)=[CH:17][CH:16]=1)=O)C1C=CC=CC=1.C(OCC)(=O)C>[C].[Pd].CO>[NH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:34]#[N:35])=[CH:20][N:21]2[C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([OH:33])[CH:25]=2)=[CH:17][CH:16]=1
Reactant: N#Cc1cn(-c2ccc(C(=O)O)c(O)c2)c2cc(OCCNC(=O)OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1cn(-c2ccc(C(=O)O)c(O)c2)c2cc(OCCN)ccc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a solution of 4-[6-(2-benzyloxycarbonylaminoethyloxy)-3-cyanoindol-1-yl]-2-hydroxybenzoic acid (0.087 g) in a mixed solvent ethyl acetate (2 mL) and methanol (2 mL) was added palladium-carbon powder (0.016 g) under an argon atmosphere at 0° C., and this mixture was stirred at 40° C. under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. This obtained light yellow solid was washed with diethyl ether, dried to give the title compound (0.058 g).
Reaction SMILES: C[O-].[K+].[CH3:4][O:5]CCOCCN(CCOCCOC)CCOCCOC.[CH2:26]([CH:28]([C:31]1[C:32]2[N:33]([C:38]([C:42]3[S:46][C:45]4[CH:47]=[CH:48][C:49](F)=[CH:50][C:44]=4[C:43]=3[CH3:52])=[C:39]([CH3:41])[N:40]=2)[N:34]=[C:35]([CH3:37])[CH:36]=1)[CH2:29][CH3:30])[CH3:27]>ClCCl.O>[CH2:26]([CH:28]([C:31]1[C:32]2[N:33]([C:38]([C:42]3[S:46][C:45]4[CH:47]=[CH:48][C:49]([O:5][CH3:4])=[CH:50][C:44]=4[C:43]=3[CH3:52])=[C:39]([CH3:41])[N:40]=2)[N:34]=[C:35]([CH3:37])[CH:36]=1)[CH2:29][CH3:30])[CH3:27]
Reactant: COCCOCCN(CCOCCOC)CCOCCOC
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Agent: C[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(OC)cc4c3C)c(C)nc12
Reaction time: 0.08 h
Yield: 293.2 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 0.014 g (0.197 mmol) of potassium methoxide and 0.005 mL (0.013 mmol) of tris[2-(2-methoxyethoxy)ethyl]amine are heated at 150° C. and stirred vigorously for 5 minutes. 0.050 g (0.131 mmol) of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-imidazo[1,2-b]pyridazine is added and the reaction is followed by TLC (2:1 Hexanes/Ethyl Acetate) and MS. After 4 h, the reaction mixture is diluted with 20 mL dichloromethane and 20 mL of water. The layers are separated and the aqueous is extracted 3×50 mL of dichloromethane, dried (MgSO4), and concentrated under vacuum. The crude mixture is purified by chromatography using hexanes:ethyl acetate as a solvent system. Combined fractions to obtain 0.015 g of the title compound, 29% yield. MS, ES+=394.2 (M+1); H1NMR (DMSO-d6) δ 7.863-7.842 (d, J=8.368, 1H); 7.327-7.321 (m, 1H); 7.076-7.049 (m, 1H); 6.991 (s, 1H); 3.857 (s, 3H); 3.094 (m, 1H); 2.477 (s, 3H); 2.350 (s, 3H); 2.180 (s, 3H); 1.853-1.760 (m, 4H); 0.793-0.757 (m, 6H) ppm.