Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C>[CH2:17]([O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1)[CH:16]=[CH2:15]
Reactant: Nc1cc(O)ccn1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccnc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
To a stirred solution of 2-aminopyridin-4-ol (500 mg, 4.5 mmol) in DMF (5 mL) at rt was added K2CO3 (940 mg, 6.8 mmol). The resulting mixture was stirred at rt for 20 min before allyl bromide (393 μL, 4.5 mmol) was added. The mixture was then stirred at rt overnight and heated at 60° C. for 2 h. After cooling to rt, the mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in hexanes to give 4-(allyloxy)pyridin-2-amine (110 mg, 16%) as a white solid. LCMS (ESI) m/z 151 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][CH3:12])=[N:7][N:8]=1.[CH2:13]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:13]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][CH3:12])=[N:7][N:8]=2)=[O:29])=[CH:31][CH:32]=1)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16]
Reactant: CCCSc1nnc(N)s1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCSc1nnc(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-propylthio-1,3,4-thiadiazole (1.2 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.9 g) and carbonyldiimidazole (1.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.3 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:43])[C:32]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38](O)[CH:37]=1)([CH3:34])[CH3:33])[CH3:29].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:28]([O:30][C:31](=[O:43])[C:32]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:37]=1)([CH3:34])[CH3:33])[CH3:29]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(O)c1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1cccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), 2-(3-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (CAS RN: 328919-24-0), tri-n-butylphosphin and N,N,N′,N′-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow solid (19%). MS (Turbo Spray): m/z=597.2 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([OH:22])=[C:14]([C:23]([N:25]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:24])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][N:3]=1.[NH2:62][NH2:63].CO>C(Cl)Cl.CC(C)=O>[NH:62]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([OH:22])=[C:14]([C:23]([N:25]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:24])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][N:3]=1)[NH2:63]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2ccc(Cl)nc2)c2ccccc2c1O
Reactant: NN
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2ccc(NN)nc2)c2ccccc2c1O

Procedure:
A mixture of 12.7 g (0.0144 mole) 4-(2-chloro-5-pyridinesulfonamido)-1-hydroxy-N,N-dioctadecyl-2-naphthamide, 4.7 g 95% hydrazine, and 413 ml methanol was heated under reflux for 17 hours. The hot mixture was filtered and then chilled. The product was filtered off, washed first with cold methanol, then with water, and air dried, yielding 11.7 g (93%), mp 96°-8° C. after softening. A thin-layer chromatogram using 85/15 methylene chloride/acetone to elute, showed traces of impurities.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[CH:4][C:3]=1[F:24].Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][C:3]=1[F:24]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3ccc(Cl)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
Trans-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (49 mg, 0.14 mmol) was dissolved in hydrogen bromide (33% in AcOH, 2 mL, 11.42 mmol) and stirred at room temperature for 5 h. The reaction was heated to 50° C. for 3 h. The reaction mixture was evaporated in vacuo and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(4-chloro-3-fluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (23 mg, 56%). 1H NMR (600 MHz, dmso) δ 1.72-1.81 (m, 2H), 1.82-1.89 (m, 1H), 1.97-2.04 (m, 1H), 2.64-2.71 (m, 1H), 2.77-2.83 (m, 1H), 3.06-3.12 (m, 1H), 3.72 (dd, 1H), 5.96 (s, 1H), 7.23 (dd, 1H), 7.40 (dd, 1H), 7.49 (t, 1H). HRMS Calculated for [C14H14ClFN2O2+H]+: 297.0806. Found: 297.0807
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](O)=[C:20]([CH:24]=1)[C:21]([NH2:23])=[O:22].N1CCCC1>CO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:23][C:21](=[O:22])[C:20]3[CH:24]=[C:16]([Br:15])[CH:17]=[CH:18][C:19]=3[O:14]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: NC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)c1cc(Br)ccc1O2
Temperature: 70 °C
Yield: 68.4 %

Procedure:
1-BOC-piperidin-3-one (4.0 g, 20 mmol) was added to a mixture of 5-bromo-2-hydroxybenzamide (2.0 g, 9.2 mmol) and pyrrolidine (0.76 ml, 9.2 mmol) in MeOH (7.5 ml), and the reaction mixture was heated to 70° C. by MW (closed vessel) for 5 h. The solution was then concentrated under vacuum and the crude mixture was purified by column chromatography on silica gel (eluent: DCM/EtOAc 7:3) to give (±)-6-bromo-3,4-dihydro-4-oxo-spiro-[2H-(1,3)-benzoxazine-2,3′-piperidine]-1′-carboxylic acid tert-butyl ester (2.50 g) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:57][C:47]=2[C:48]([N:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)=[N:49][CH:50]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 386 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)CCCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
To a mixture of 0.206 g (2 mmole) of 3-dimethylamino-propan-1-ol, and 2 mL of pyridine (2 ml) was added 0.001 g of 4-dimethylaminopyridine and 0.381 g (2 mmole) of p-toluenesulphonyl chloride. The mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was taken up in 10 mL of dichloromethane and washed once with 5 mL of saturated sodium bicarbonate, twice with 5 mL of water, and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.085 g of toluene-4-sulfonic acid 3-dimethylamino-propyl ester as a colorless oil.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([I:21])=[CH:23][CH:24]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: O=Cc1ccc(I)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Ic1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 81.4 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.04 g, 0.15 mmol) was reacted with 4-iodobenzaldehyde (0.045 g, 0.15 mmol) in the presence of glacial acetic acid (0.009 g, 0.15 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.012 g, 0.18 mmol) in methanol (5 ml) (Procedure D) to give compound 16m (0.059 g, 81%) as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:17][C:16]3[CH:18]=[CH:19][C:20](I)=[CH:21][C:15]=3[S:14](=[O:24])(=[O:23])[N:13]=2)=[C:8]([OH:25])[C:7]2=[CH:26][CH:27]=[CH:28][N:6]12.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].N(CC(O)=O)C.[CH3:55][NH:56][S:57]([CH3:60])(=[O:59])=[O:58]>C(OCC)(=O)C.[Cu].[Cu]I.CN(C)C=O>[CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([N:56]([CH3:55])[S:57]([CH3:60])(=[O:59])=[O:58])=[CH:21][C:15]=3[S:14](=[O:24])(=[O:23])[N:13]=2)=[C:8]([OH:25])[C:7]2=[CH:26][CH:27]=[CH:28][N:6]12
Reactant: CC(C)(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Reactant: CNS(C)(=O)=O
Agent: [Cu]
Agent: [Cu]I
Agent: CNCC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccn3n(CCC(C)(C)C)c1=O)N2)S(C)(=O)=O
Yield: 33 %

Procedure:
1-(3,3-Dimethyl-butyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-pyrrolo[1,2-b]pyridazin-2-one (Example 4d, 0.257 g, 0.476 mmol), potassium triphosphate (0.505 g, 2.38 mmol), sarcosine (0.025 g, 0.285 mmol), and copper (J) iodide (0.022 g, 0.119 mmol) were combined. Anhydrous N,N-dimethylformamide (9.5 mL) was added followed by N-methyl-methanesulfonamide (0.519 g, 4.76 mmol). The solution was degassed while stirring under vacuum and the flask purged with nitrogen. The mixture was stirred at 100° C. for 1 h. Additional copper (I) iodide (0.1 g, 0.525 mmol) was added. The mixture continued to stir at 100° C. for 3 h. Upon cooling, the mixture was diluted with ethyl acetate (200 mL), washed with 1.0 M aqueous hydrochloric acid solution (2×100 mL), dried over magnesium sulfate. The entire organic layer was passed through a plug of silica gel. Upon concentrating in vacuo to a volume of approximately 10 mL, the desired product precipitated. The solid was collected by vacuum filtration. The solid was recrystallized in ethyl acetate, collected by vacuum filtration and dried in vacuo to afford the desired product, N-{3-[1-(3,3-dimethyl-butyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (0.082 g, 0.157 mmol, 33% yield) as a pale yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.02 (9H, s), 1.58-1.62 (2H, m), 3.01 (3H, s), 3.31 (3H, s), 4.40-4.44 (2H, m), 6.72-6.72 (1H, m), 7.04 (1H, d, J=3.9 Hz), 7.70-7.76 (3H, m), 7.88 (1H, s), 13.78 (1H, bs). LC-MS (ESI) calcd for C22H27N5O6S2. found 521.14. found 522.6 [M+H+].
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[C:9]#[N:10]>CCO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([C:9](=[N:1][OH:2])[NH2:10])[CH:11]=1
Reactant: NO
Reactant: COc1ccc(F)cc1C#N
Solvent: CCO
Product: COc1ccc(F)cc1C(N)=NO
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Hydroxylamine (4.97 ml; 82.7 mmol; 5 eq.) was added to a suspension of 5-fluoro-2-methoxybenzonitrile (Aldrich 527734; 2.5 g; 16.5 mmol; 1 eq.) in EtOH (30 mL) and the resulting mixture was stirred at room temperature for 3 days then to dryness to afford the title compound (3.04 g, 100%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH2:21][OH:22])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.[O-2].[Mn+2]>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH:21]=[O:22])=[CH:8][CH:7]=1
Reactant: CN(C)CCNc1ccc(CO)c2sc3ccccc3c(=O)c12
Agent: [Mn+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CN(C)CCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Temperature: 60 °C
Yield: 86.4 %

Procedure:
A mixture of 1-[[2-(dimethylamino)ethyl]amino]-4-(hydroxymethyl)-thioxanthen-9-one (9.2 g, 0.028 mol) in toluene (322 mL) was heated to about 60° C. and then manganese oxide (MnO2, 16 g) was added and the mixture was heated at 60° C. for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to afford 7.9 g (87%) of 1-[[2-(dimethylamino)-ethyl]amino]-9-oxothioxanthen-4-carboxaldehyde (Formula II: R1 =R2 =Me; R8 =H; n=2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:11]1[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=1>CN(C)C=O>[O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:11]2[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=2)[CH:4]=[CH:3]1
Reactant: Oc1ccncc1
Reactant: O=Cc1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccc(=O)cc2)s1
Reaction time: 1 h

Procedure:
25.0 g of 4-hydroxypyridine was suspended in 440 ml of N,N-dimethylformamide. 11.04 g of sodium hydride (60% suspension in mineral oil) was added to the suspension in portions and the suspension was stirred for 1 h. 32.8 ml of 5-bromothiophene-2-carboxaldehyde was added thereto and a reaction was conducted at 120° C. for 4 h.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:29])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(Cl)C1CCCCC1
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCCC1
Yield: 84.2 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) was reacted with cyclohexanecarbonyl chloride (0.52 mL, 3.9 mmol) to provide 1.16 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclohexanecarboxamide as a light brown solid, m.p. 201.7-202.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Product: CCOC(=O)c1nc(N2CCNCC2)n(C)c(=O)c1OCc1ccccc1
Yield: 0.6 %

Procedure:
Following the procedure described for the synthesis of compound 67A 5-Benzyloxy-2-methanesulfonyl-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (7.0 g, 19.2 mmol) was reacted with piperazine (17.0 g, 192 mmol) and to yield the title compound as a pale yellow oil (0.0418 g, 42% yield). 1H NMR (500 MHz, CDCl3) δ: 7.45 (2H, d, J=6.7 Hz), 7.34–7.27 (3H, m), 5.13 (2H, s), 4.30 (2H, q, J=7.2 Hz), 3.49 (3H, s), 3.15–3.13 (4H, m), 2.98–2.96 (4H, m), 1.89 ( 1H, bs), 1.27 (3H, J=7.2 Hz). HRMS (M+H) calcd for C19H25N4O4: 373.21414. found: 373.1866.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:15]5[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=5[O:13][CH2:12][C:11]4=[O:21])[CH2:6][CH2:7]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: NC1CCN(CCN2C(=O)COc3ccc(F)cc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(F)cc2N1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Yield: 32.3 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 54) (0.7 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (140 mg, 0.84 mmol), and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21 to give 100 mg (32%) product.
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[I-].[Na+].CO>C1COCC1.C(Cl)Cl>[CH3:9][C:3]1([CH2:2][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: CC1(CCl)COC(=O)N1
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC1(CN2CCCC2)COC(=O)N1
Temperature: 85 °C
Yield: 35.1 %

Procedure:
To a solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (1.41 g, 9.43 mmol) in THF (40 ml) was added pyrrolidine (5.0 ml, 61 mmol) and sodium iodide (1.03 g, 6.87 mmol). The solution was sealed, heated to 85° C. for 24 h, cooled to RT, filtered, and concentrated in vacuo. Flash chromatography (2%→12% MeOH in CH2Cl2) afforded the oxazolidinone (609.8 mg, 3.31 mmol, 35%) as a brown oil which solidified upon standing. The dihydrooxazole was isolated in roughly 75% purity (1.8 g crude yield) and was characterized only by MS. 1H NMR (CDCl3, 400 MHz) δ 1.35 (s, 3H), 1.7-1.8 (m, 4H), 2.5-2.7 (m, 6H), 4.02 (d, J=8.4 Hz, 1H), 4.24 (d, J=8.4 Hz, 1H), 5.3-5.4 (br s, 1H). ESI/APCI expected for C9H16N2O2: 184.12. Found: 185 (MH+). 1H NMR (CDCl3, 400 MHz) δ 1.35 (s, 3H), 1.7-1.8 (m, 4H), 2.5-2.7 (m, 6H), 4.02 (d, J=8.4 Hz, 1H), 4.24 (d, J=8.4 Hz, 1H), 5.3-5.4 (br s, 1H). ESI/APCI expected for C9H16N2O2: 184.12. Found: 185 (MH+).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:28])[CH2:14]/[C:15](=[CH:19]\[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)/[C:16]([OH:18])=[O:17])([CH3:11])([CH3:10])[CH3:9]>CO>[CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:28])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]([OH:18])=[O:17])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)C/C(=C\CCc1ccccc1)C(=O)O
Solvent: NC1CCCCC1
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A stirred solution of cyclohexylamine (266 ml, 2.32 mol), (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (688 g, 2.37 mol) and [(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)ruthenium chloride (4.4 g, 4.7 mmol) in methanol (6.9 liters) was heated to 60° C., under hydrogen (60 p.s.i.), for 47 hours and then allowed to cool to 20-25° C. (enantiomeric excess=88%). The mixture was filtered through a filter aid Celite® and then the solvent was stripped and replaced with acetone by distillation at atmospheric pressure, at a constant volume of 4.2 liters. The resulting suspension was cooled to 20-25° C., stirred for 4 hours and then filtered. The residue was washed with acetone (2× 1 liter) and then dried in vacuo at 45° C. for 16 hours to leave the title compound as a colourless solid (590 g, 64% yield, enantiomeric excess=98.9%, 97% pure by HPLC).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[N+:1]([C:4](=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][S:6]1)[C:11](=[O:13])[CH3:12])([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])C=C1NCCCS1
Product: CC(=O)C(=C1NCCCS1)[N+](=O)[O-]

Procedure:
4.0 g of 2b was added in portions to 50 ml of acetic anhydride at 25°. The solution was heated at 95°-105° for 2 hours. Excess acetic anhydride was removed under reduced pressure to leave 5.0 g of a slightly gummy brown solid which was crystallized from ethyl acetate (after treatment with charcoal) to give 2 as a yellow-brown solid, m.p.: 110°-113°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(N)nc3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl (example E.26) (0.150 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.092 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.080 g, 51%). MS (ISP) 407.3 [(M+H)+]; mp 208-211° C.