Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([CH2:8][OH:9])[O:6][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4]1.[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:9][CH2:8][C@H:7]1[C@H:3]([CH2:2][O:1][CH2:5][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: OC[C@@H]1OC(c2ccccc2)O[C@H]1CO
Agent: [K+]
Agent: [OH-]
Product: c1ccc(COC[C@@H]2OC(c3ccccc3)O[C@H]2COCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
15 g (71.4 mMol) (4S,5S)-4,5-dihydroxymethyl-2-phenyl-1,3-dioxolan are rendered completely anhydrous by evaporating 2× with 300 ml toluene and the oil remaining in the reaction vessel is dissolved in 150 ml toluene, 30 g powdered KOH (535 mMol) and 71.5 g (418 mMol) benzyl bromide are added and the reaction mixture stirred for 15 hours at 80° C. The mixture is cooled, the remaining toluene-phase decanted, and the inorganic component removed from the residual phase by stirring 2× with 200 ml toluene and decanting. The combined toluene phases are filtered through talc, evaporated and the remaining oil filtered fraction-wise through 2 kg silica gel 60 using methylene chloride as solvent. Fractions containing benzyl bromide are disposed of. The title compound is obtained as a light yellow fluid with a rotation of [α]D20 =+10.1 (±1)° (c=1.4 in chloroform).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:17])[NH:10][CH2:11][C@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[C:23]([C@H:30]3[CH2:32][O:31]3)[CH:24]=[CH:25][N:26]=2)[N:21]=1>CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:17])[NH:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH2:32][C@@H:30]([OH:31])[C:23]3[C:22]4[C:27](=[CH:28][CH:29]=[C:20]([O:19][CH3:18])[N:21]=4)[N:26]=[CH:25][CH:24]=3)[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC[C@H]1CCNC1)OCc1ccccc1
Reactant: COc1ccc2nccc([C@H]3CO3)c2n1
Solvent: CN(C)C=O
Product: COc1ccc2nccc([C@H](O)CN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Reaction time: 24 h
Yield: 24.4 %

Procedure:
To a solution of phenylmethyl[(3S)-3-pyrrolidinylmethyl]carbamate (0.53 g, 2.27 mmole) and LiClO4 (0.24 g, 2.27 mmole) in DMF (1 mL) was added 2-(methyloxy)-8-[(2S)-2-oxiranyl]-1,5-naphthyridine (0.45 g, 2.25 mmole). After 24 h at 80° C., the reaction contents were purified on silica gel (CHCl3/MeOH, 9:1, containing 5% NH4OH) to afford the title compound (0.24 g, 25%) as a light yellow oil: LC-MS (ES) m/e 437 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20]1([CH2:26][C:27]([NH:29][NH2:30])=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N#N>C(O)CCC>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:27]([CH2:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:29][N:30]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(I)ccc2N1
Reactant: NNC(=O)Cc1ccccc1
Agent: N#N
Solvent: CCCCO
Product: Ic1ccc2c(c1)C(c1ccccc1)=NCc1nnc(Cc3ccccc3)n1-2

Procedure:
A stirred mixture of 7-iodo-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione (3.78 g, 0.01 mol), phenylacetic acid hydrazide (4.5 g, 0.03 mol) and butanol (150 ml) was heated to reflux while N2 was bubbled through the mixture. After refluxing 17 hours the reaction mixture was concentrated under vacuum. The residue was combined with ice water and allowed to stir for a few minutes. The resulting suspension was filtered and the filtered material washed with CH2Cl2. The filtrate was separated into its respective layers and the aqueous layer washed with CH2Cl2. The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was triturated with EtOAc to yield 1.43 g (30.04%), mp 200°-201° of the subtitled intermediate. The analytical sample was recrystallized from EtOAc and had mp 201°-202°. The IR, NMR and mass spectra supported the proposed structure.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:19](=[O:25])[CH2:20][C:21](OC)=[O:22])=[C:10]([C:15]([O:17][CH3:18])=[O:16])[N:11]2[CH3:14])=[CH:7][CH:6]=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:21](=[O:22])[CH2:20][C:19]([C:9]1[C:8]2[C:12](=[CH:13][C:5]([F:4])=[CH:6][CH:7]=2)[N:11]([CH3:14])[C:10]=1[C:15]([O:17][CH3:18])=[O:16])=[O:25]
Reactant: CNC
Reactant: COC(=O)CC(=O)c1c(C(=O)OC)n(C)c2cc(F)ccc12
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C(=O)CC(=O)N(C)C)c2ccc(F)cc2n1C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A stream of gaseous dimethylamine is passed into a mixture of 13 g (44.4 mmol) of methyl 3-[6-fluoro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxo-propanoate, obtained in step 1.2., and 0.2 g (1.63 mmol) of 4-(N,N-dimethyl)aminopyridine in 80 ml of toluene. Immediately a condenser, surmounted by a balloon flask, is fitted and the solution is stirred at 100° C. for 20 h. The mixture is cooled to ambient temperature and concentrated under reduced pressure. 200 ml of dichloromethane, water and hydrochloric acid (1N) are added. The organic phase is separated off, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column (eluent: cyclohexane/dichloromethane: 50/50, then dichloromethane/ethyl acetate 100/0 to 0/100).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[CH:14]([OH:17])[CH2:15][CH3:16].[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>CCCCC.C1COCC1>[F:13][C:9]1[C:8]([CH:14]([OH:17])[CH2:15][CH3:16])=[C:7]([B:18]([OH:23])[OH:19])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCC(O)c1c(F)cccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCC(O)c1c(F)cccc1B(O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of n-BuLi (2.15 mL, 4.3 mmol) in pentane (2 M) is added dropwise to a solution of 1-(2-bromo-6-fluoro-phenyl)-propan-1-ol (500 mg, 2.15 mmol) in THF at −78° C. The mixture is stirred for 2 hours at −78° C. (i-PrO)3B (41 mL, 4.3 mmol) is added in one portion and the mixture is warmed slowly to room temperature and stirred for 12 hours. 1N HCl (10 mL) is added and the mixture is stirred for 2 hours at room temperature. The organic layer is separated and the aqueous layer is extracted with DCM (3×30 mL). The combined organic layers are dried and solvents are removed in vacuo. The crude product is purified by PTLC eluting with 5% MeOH in DCM to give 3-fluoro-2-(1-hydroxypropyl)phenylboronic acid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[OH:17].[NH3:19]>>[OH:17][C:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:9][C:4]=1[C:3]([NH2:19])=[O:2]
Reactant: N
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)ccc1O
Product: NC(=O)c1cc(-c2ccc(F)cc2)ccc1O

Procedure:
A mixture of 5.3 grams of methyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate and 20 ml. of liquid ammonia is reacted in a bomb at 100° C. for 4 hours. After cooling the bomb is opened and the ammonia allowed to evaporate. The residue is then recrystallized from benzene to yield 2-hydroxy-5-(4'-fluorophenyl)-benzamide (m.p. 206° - 207° C.).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH2:12]([O:14][C:15](=[O:22])[CH:16]([CH2:20][OH:21])[CH2:17][CH2:18]Br)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:14][C:15](=[O:22])[CH:16]([CH2:20][OH:21])[CH2:17][CH2:18][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:11])[CH3:13]
Reactant: CCOC(=O)C(CO)CCBr
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CO)CCn1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 92 h
Yield: 15.9 %

Procedure:
2-Amino-6-chloropurine (3.37 g, 19.9 mmol), 4-bromo-2-hydroxymethylbutyric acid ethyl ester (4.49 g, 19.9 mmol) and anhydrous potassium carbonate (2.75 g, 19.9 mmol) were mixed with 50 ml of dimethylformamide and the mixture was stirred at room temperature during 92 hours. The mixture was then filtered and the filtrate evaporated. The residue was extracted with 3×50 ml chloroform and the combined extracts were evaporated. Flash chromatography (silica gel, chloroform-methanol 10:1) and two recrystallizations from water afforded 0.995 g of the 4-(2-amino-6-chloropurin-9-yl)-2-hydroxymethylbutyric acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15](O)=[O:16])[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15]([N:65]2[CH2:70][CH2:69][O:68][CH2:67][CH2:66]2)=[O:16])[N:7]=1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)O)N2)n1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)N3CCOCC3)N2)n1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
To a solution of (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetic acid (105d, 0.05 mmol, 22.6 mg) in DMF (0.5 mL) was added HBTU (0.075 mmol, 28 mg), Et3N (0.125 mmol, 17 μL) and morpholine (0.1 mmol, 8.3 μL). The reaction mixture was stirred over night at r.t. and LCMS shows completion of the reaction. Purified by prep LCMS to afford the title compound (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-morpholinoethanone (102, 5.7 mg, 22%) as off white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.83 (s, 3H) 3.15 (dd, J=17.31, 10.23 Hz, 2H) 3.43-3.51 (m, 2H) 3.63 (d, J=5.31 Hz, 2H) 3.65-3.71 (m, 4H) 3.89 (s, 3H) 4.71 (s, 2H) 4.97 (dd, J=10.36, 3.79 Hz, 1H) 5.96 (br. s., 1H) 6.77 (d, J=8.34 Hz, 1H) 7.03 (d, J=7.07 Hz, 1H) 7.14 (dd, J=9.35, 2.78 Hz, 1H) 7.19 (td, J=8.40, 2.65 Hz, 1H) 7.63 (dd, J=8.84, 5.56 Hz, 1H) 7.68 (dd, J=8.34, 7.33 Hz, 1H). MS (ES) [M+H] calculated for C26H28FN7O4, 522.22; found 522.00.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[C:10]2=[N:23][C:24]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)=[CH:25][C:26](=[O:27])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)=[CH:17][CH:16]=2)[C:10]2=[N:23][C:24]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)=[CH:25][C:26](=[O:27])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NC(=O)c2ccc(Br)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NC(=O)c2ccc(-c3cnn(C)c3)cc2)C1
Temperature: 90 °C
Reaction time: 15 h
Yield: 61.1 %

Procedure:
A mixture containing 0.145 g (0.28 mmol) of 9-(4-bromo-benzoylamino)-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester (example 10), 0.082 g (0.40 mmol) of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester, 0.35 mL (0.71 mmol) of sodium carbonate (solution 2M), 0.065 g (0.06 mmol) of tetrakis(tri-phenylphosphine)palladium in 5.60 mL of toluene/EtOH (10/1) under argon atmosphere was stirred at 90° C. for 15 hours. The reaction mixture was cooled, aqueous saturated solution of sodium carbonate was added and the resulting solution extracted with dichloromethane. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 98/2/0.2 to 97/3/0.3 to afford 0.088 g (76%) of the pure product as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[C:9](O)=O)[CH:5]=[CH:6][CH:7]=1.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>>[NH:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:20]=[C:9]1[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:12]
Reactant: Nc1ccccc1N
Reactant: O=C(O)C(O)c1cccc(Br)c1
Product: OC(c1cccc(Br)c1)c1nc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of (3-bromophenyl)hydroxyacetic acid (20 g) and ortho-phenylenediamine (9.36 g) in 5N aqueous hydrochloric solution (100 mL) is heated under reflux for 4 h and cooled back to room temperature. The precipitate is separated by filtration, rinsed with acetonitrile and dried under vacuum with phosphorus pentoxide et give 1H-benzimidazol-2-yl(3-bromophenyl)methanol as a white crystalline solid used without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[CH:9]1[C:17]2[C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[O:14][C:13]=2[CH:12]=[CH:11][C:10]=1[NH2:22]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([NH:22][C:10]1[CH:11]=[CH:12][C:13]2[O:14][C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][C:16]=3[C:17]=2[CH:9]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc2oc3c(c2c1)CCCC3
Reactant: CCN(CC)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)Nc1ccc2oc3c(c2c1)CCCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
Diethylcarbamoyl chloride (0.72 mL, 5.5 mmol) was added to a solution of 6,7,8,9-tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol) in pyridine (15 mL). The reaction mixture was stirred overnight at room temperature. The crude material was diluted in chloroform and washed with 1 N HCl, water, and brine, dried (Na2SO4) and concentrated. The crude material was recrystallized from acetonitrile to provide 1,1-diethyl-3-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-urea (0.78 g). Mp 179-180° C.; Anal. Calcd. for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78; Found: C, 71.29; H, 7.66; N, 9.72.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][S:45]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:47])=[O:46])[CH:29]=3
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)c1ccccc1
Yield: 42 %

Procedure:
The desired compound was prepared according to the procedure of Example B136, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and benzenesulfonyl chloride as the starting materials in 42% yield. LCMS for C24H21ClN5O2S (M+H)+: m/z=478.1. 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.55 (s, 1H), 9.50 (s, 1H), 8.15 (s, 1H), 7.76 (m, 3H), 7.50 (m, 3H), 7.40 (m, 1H), 7.10 (dd, 1H), 6.94 (m, 1H), 6.88 (m, 1H), 6.80 (m, 1H), 6.69 (m, 1H), 2.74 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].[CH:23]1([CH:29]=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:10])[CH3:11])[C:7]=1[CH3:8]
Reactant: O=CC1CCCCC1
Reactant: Cc1c(Cl)cc(C(=O)NCC2CCNCC2)c(=O)n1C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)NCC2CCN(CC3CCCCC3)CC2)c(=O)n1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a stirred solution of 5-chloro-1-isopropyl-6-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydropyridine-3-carboxamide as prepared in 6(2) (228 mg, 0.70 mmol), cyclohexanecarboxaldehyde (94 mg, 0.84 mmol) in dichloromethane (11 mL) was added sodium triacetoxyborohydride (312 mg, 1.40 mmol) at room temperature, and the mixture was stirred at room temperature for 4 h. The mixture was quenched with saturated sodium hydrogencarbonate aqueous solution (80 mL), extracted with dichloromethane (50 mL×4). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1) to give 213 mg (72%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:9]2[O:10][C:11]([CH3:14])=[C:12]([CH3:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:17])=O>CN(C)C=O>[Cl:17][C:1]([C:4]1[C:9]2[O:10][C:11]([CH3:14])=[C:12]([CH3:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: Cc1oc2c(C(=O)O)cccc2c1C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1oc2c(C(=O)Cl)cccc2c1C

Procedure:
A mixture of 7-carboxy-2,3-dimethylbenzo[b]furan (2 g) and N,N-dimethylformamide (1 drop) in thionyl chloride (10 ml) was refluxed for 2 hours. The reaction mixture was cooled and concentrated in vacuo. The crystalline residue was triturated with n-hexane to give 7-chlorocarbonyl-2,3-dimethylbenzo[b]furan (2.17 g).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][Cl:12]>C1COCC1.O>[Cl:12][CH2:11][CH2:10][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1
Reactant: ClCCBr
Reactant: Ic1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: ClCCn1cnc(I)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a stirred solution of 4-iodoimidazole (8.8 g, 45.4 mmol) in THF (200 mL) at 0° C. under nitrogen was added portion-wise NaH 60% (1.99 g, 49.9 mmol). After 15 min, 1-bromo-2-chloroethane (4.53 mL, 54.4 mmol) was added at 0° C. The reaction mixture was heated at 60° C. for 20 h. After cooling to RT, the reaction mixture was diluted with water and extracted with AcOEt. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340 g cartridge; MeOH/AcOEt: 0/100 to 5/95 over 20 CV), to afford crude 1-(2-chloroethyl)-4-iodo-1H-imidazole not shown in the scheme 57 (7 g, 27.26 mmol, 60% yield) as colorless oil. MS (m/z): 256.83 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](SC)=[N:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:20])[CH2:3]1>CN(C)C=O.[Ni]>[N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:8]([C:7]3[CH:2]([CH3:1])[CH2:3][C:4](=[O:20])[NH:5][N:6]=3)[CH:17]=2)[CH2:12][NH:13][CH:14]=1
Reactant: CSc1ncnc2cc(C3=NNC(=O)CC3C)ccc12
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc2c(c1)N=CNC2
Temperature: 60 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
In 10 ml of dimethylformamide was dissolved 1.0 g of Compound 57 obtained in Example 19, and 5.0 g of Raney nickel was added to the solution, followed by stirring at 60° C. for 1 hour. The catalyst was filtered off, and the filtrate was concentrated. Water was added to the residue, and the crystals precipitated were collected by filtration and dried to give 0.22 g (26%) of 4,5-dihydro-6-(3,4-dihydroquinazolin-7-yl)-5-methyl-3(2H)-pyridazinone (Compound 71).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[CH2:15]([O:18][NH2:19])[CH:16]=[CH2:17]>>[CH2:15]([O:18][N:19]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11])[CH:16]=[CH2:17]
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Reactant: C=CCON
Agent: Cl
Product: C=CCON=C(C(=O)O)c1ccc(O)c(Cl)c1
Yield: 98.1 %

Procedure:
2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2 g.) and O-allylhydroxylamine hydrochloride (1.1 g.) were reacted according to a similar manner to that of Preparation (5-2)(a) to give oil of 2-allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.5 g.).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8].Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.Cl>CN(C)C=O>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([S:3][C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])=[N:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=C(O)c1cccc(S)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2cccc(C(=O)O)c2)nc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
Add sodium hydride (60% dispersion in mineral oil, 635 mg, 15.88 mmol) to a solution of 3-mercapto-benzoic acid (1.11 g, 7.22 mmol) in dimethylformamide (50 mL) chilled to 0° C. and stir. After 10 minutes add 6-chloro-nicotinonitrile (1.00 g, 7.22 mmol). Warm gradually to ambient temperature. After 18 hours, add 1N aqueous hydrochloric acid (200 mL). Filter resulting precipitate, washing with water and hexanes to yield the title compound as a tan solid (1.25 g, 68%): 1H NMR (DMSO-d6) δ 7.22 (d, 1H), 7.67 (t, 1H), 7.88 (dt, 1H), 8.07-8.12 (m, 3H), 8.82 (dd, 1H), 13.30 (bs, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[K+].C(O)C>O>[CH2:12]([C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1c(CCc2ccccc2)noc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1onc(CCc2ccccc2)c1C(=O)O

Procedure:
A mixture of 300 g. (1.30 mole) 3-phenethyl-5-methyl-isoxazole-4-carboxylic acid ethyl ester, 146 g. (1.60 mole) potassium hydroxide 1500 ml. ethanol and 500 ml. water is stirred for 2 hours at room temperature and 2 additional hours at reflux. The ethanol is evaporated in vacuo and the aqueous solution is cooled and acidified with hydrochloric acid. The resulting solid is filtered and washed with water and triturated with methanol to give 3-phenethyl-5-methyl-isoxazole-4-carboxylic acid; m.p. 154° to 156° C.