Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](O)=[O:33])[CH:27]=[CH:28][C:29]=1[F:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[N:18][C:19]=5[NH2:21])[N:14]([CH3:22])[N:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:33])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2ccc(F)c(Cl)c2)c2c(N)ncnc21
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (64.6 mg, 0.190 mmol), (3-chloro-4-fluorophenyl)acetic acid (35.9 mg, 0.190 mmol), HATU (72.4 mg, 0.190 mmol) in DMF (2 mL) was added Hunig's base (0.133 mL, 0.762 mmol). The mixture was stirred overnight. The reaction was poured into water, and an off-white solid formed. The solid was filtered to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.22-3.30 (m, 2H), 3.94 (s, 5H), 4.26 (t, J=8.46 Hz, 2H), 7.33 (dd, J=4.93, 2.15 Hz, 1H), 7.37-7.40 (m, 1H), 7.41-7.47 (m, 1H), 7.51-7.58 (m, 2H), 8.18 (d, J=8.59 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:10][N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2-c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2nn(-c3ccccc3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 4-(4-methoxy-1-phenyl-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (82.0 mg) in acetonitrile (10 mL) were added sodium iodide (64.6 mg) and chloro(trimethyl)silane (0.218 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol), and the obtained solid was washed with ethyl acetate to give the title compound (79.0 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O[C:28]1[CH:29]=[CH:30][C:31]2[CH2:37][CH2:36][CH2:35][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:33][C:32]=2[CH:42]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:20]1([O:26][C:28]2[CH:29]=[CH:30][C:31]3[CH2:37][CH2:36][CH2:35][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:33][C:32]=3[CH:42]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Reactant: OC1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(OC3CCCCC3)ccc2CCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
To triphenylphosphine (1.18 g, 4.50 mmol), cyclohexanol (0.468 ml, 4.50 mmol) and methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) dissolved in THF (6 ml) was added at 0° C. a solution of diisopropyl azodicarboxylate (0.886 ml, 4.50 mmol) in THF (4 ml), and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography (silica gel: 45 g, ethyl acetate/hexane=1/25). The objective fractions were concentrated under reduced pressure to obtain methyl 2-cyclohexyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (434 mg, 1.44 mmol, 96%).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[NH:7][CH:6](O)[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[CH2:13]=O>O.[Pt]>[CH3:13][N:7]1[C@H:2]([CH2:1][OH:12])[C@@H:3]([OH:11])[C@H:4]([OH:10])[C@@H:5]([OH:9])[CH2:6]1
Reactant: OC[C@H]1NC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C=O
Agent: [Pt]
Solvent: O
Product: CN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
Yield: 85 %

Procedure:
179 mg of nojirimycin is dissolved in 20 ml of water, followed by adding 1 ml of formalin, adding 100 mg of platinum on carbon catalyst and carrying out a catalytic reduction at ordinary temperature and under atmospheric pressure. The following treatments are carried out in the same manner as in Example 2 to obtain 150 mg (85%) of N-methyl moranoline.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[C:23]=1[CH3:31]>>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[C:23]=2[CH3:31])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cccc([N+](=O)[O-])c1C)OCC

Procedure:
Analogously to the process described in Example 64A/Step 1, 1.0 g (3.62 mmol) of the compound of Example 4A and 860 mg (3.98 mmol) of 2-bromo-6-nitrotoluene gave 1.45 g (97% of theory) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Br[CH2:31][CH:32]1[O:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[O:34][CH2:33]1>>[O:37]1[C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[O:34][CH2:33][CH:32]1[CH2:31][N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:9]=2[CH3:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:27])=[O:26]
Reactant: BrCC1COc2ccccc2O1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CC2COc3ccccc3O2)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 2-bromomethyl-2,3-dihydro-benzo[1,4]dioxine. MS: ESI (negative): 503 (M−H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[OH:12][CH2:13][CH:14]([CH2:16]O)[OH:15].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC1C=CC=CC=1.O>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:15][CH:14]([CH2:13][OH:12])[CH2:16][O:4]1
Reactant: OCC(O)CO
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCC1COC(CBr)(c2ccc(Cl)cc2)O1

Procedure:
A mixture of 2-bromo-1-(4-chlorophenyl)ethanone (1.47 mol), glycerine (3.5 mol) and 4-methylbenzenesulfonic acid (0.25 mol) in methylbenzene (3000 ml) was stirred and refluxed for 24 hours, using a water separator. The reaction mixture was poured out into an aqueous NaHCO3 solution and stirred for a while. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 485 g (93%; oil) of (cis +trans)-2-(bromomethyl)-2-(4-chlorophenyl)-1,3-dioxolane-4-methanol (interm. 8a).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[ClH:27]>CO>[ClH:27].[NH:17]1[CH2:18][CH2:19][CH:14]([O:13][C:8]2[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncccc2C2CCOCC2)CC1
Agent: Cl
Solvent: CO
Product: c1cnc(OC2CCNCC2)c(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To tert-butyl 4-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)piperidine-1-carboxylate (3.2 g, 8.8 mmol) was added 4 M HCl in MeOH (100 mL). The solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the title compound (2 g, 9.8 mmol, yield 95%). ESI-MS (M+1): 263 calc. for C15H22N2O2 262.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[F:30])=[CH:22][C:21]([NH2:31])=[C:20]([NH2:32])[N:19]=1>>[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[N:19]=[C:20]2[NH:32][C:6]([C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)=[N:31][C:21]2=[CH:22][C:23]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[F:30]
Reactant: Nc1cc(-c2ccncc2F)c(-c2ccncc2Cl)nc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Product: Fc1ccc(-c2nc3cc(-c4ccncc4F)c(-c4ccncc4Cl)nc3[nH]2)cc1

Procedure:
Following the same protocol as in Example 2, but using 4-fluorobenzoylchloride and 3-chloro-3″-fluoro-4,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 8), the title compound was obtained as a white solid (13 mg, 12%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[N:4][O:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:20](OC(=O)C)(=O)C>C(OCC)(OCC)OCC>[CH3:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([C:3]2[C:2]3[N:1]=[CH:20][N:9]=[C:7]([OH:8])[C:6]=3[O:5][N:4]=2)=[CH:15][CH:14]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2noc(C(N)=O)c2N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CS(=O)(=O)c1ccc(-c2noc3c(O)ncnc23)cc1
Temperature: 25 °C

Procedure:
To a suspension of 4-amino-3-(4-methanesulfonyl-phenyl)-isoxazole-5-carboxylic acid amide (2.5 g, 8.9 mmol) in CH(OEt)3 (30 mL), was added acetic anhydride (10 mL) at ambient temperature. The reaction was heated to reflux for 5 h and cooled to room temperature. The reaction was concentrated under vacuum and poured into H2O (50 mL). The organic material was extracted with ethyl acetate (50 mL), dried over MgSO4 and concentrated under vacuum. The crude product was used for the next step without further purification. LCMS 292.0 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][N:13]([CH3:27])[CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:16][CH2:15]1>>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:17]2[CH2:18][CH2:19][CH:14]([N:13]([CH3:27])[CH3:12])[CH2:15][CH:16]=2)[CH:21]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CN(C)C1CC=C(c2cccc(N)c2)CC1
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Product: Cl
Yield: 138.4 %

Procedure:
Using a method similar to example 1, using 2-chloro-4-fluorobenzoyl chloride (128 mg, 0.66 mmol) and 3-(4-dimethylamino-cyclohex-1-enyl)-phenylamine (preparation 2, 119 mg, 0.55 mmol) provides the title compound (free base 187 mg, 91%). Free base: MS (ES): m/z=373.2 (M+H)+; 1H NMR (CDCl3): δ 8.08 (s, br, 1H), 7.77 (m, 1H), 7.68 (s, br, 1H), 7.52 (d, 1H), 7.32 (t, 1H), 7.19 (m, 2H), 7.09 (m, 1H), 6.11 (m, 1H), 2.51 (m, 4H), 2.36 (s, 6H), 2.14 (m, 2H), 1.57 (m, 1H). Hydrochloride salt: Anal. cal'd for C21H22ClFN2O.HCl.0.5H2O: C, 60.29; H, 5.78; N, 6.70. Found: C, 60.17; H, 5.45; N, 6.65.
Reaction SMILES: [C:1]([OH:4])(=[O:3])C.[CH:5]([C:8]1[S:9][CH:10]=[C:11]([C:13]([N:15]2[CH2:20][C:19]3([CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](=O)[CH3:35])[CH2:22][CH2:21]3)[O:18][CH2:17][CH2:16]2)=[O:14])[N:12]=1)([CH3:7])[CH3:6].C(O)(=O)C.[NH2:41][CH2:42][C@@H:43]([C:45]1[C:53]2[S:52][C:51](=[O:54])[NH:50][C:49]=2[C:48]([OH:55])=[CH:47][CH:46]=1)[OH:44].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:1]([OH:4])=[O:3].[OH:55][C:48]1[C:49]2[NH:50][C:51](=[O:54])[S:52][C:53]=2[C:45]([C@@H:43]([OH:44])[CH2:42][NH:41][CH:34]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][C:19]3([O:18][CH2:17][CH2:16][N:15]([C:13]([C:11]4[N:12]=[C:8]([CH:5]([CH3:6])[CH3:7])[S:9][CH:10]=4)=[O:14])[CH2:20]3)[CH2:25][CH2:24]2)[CH3:35])=[CH:46][CH:47]=1
Reactant: CC(=O)CCCCCCCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC(CCCCCCCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2)NC[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Product: O=CO
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Acetic acid (0.053 mL) was added to a mixture of 10-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)decan-2-one (example 280, step c) (335 mg) and (R)-7-(2-amino-1-hydroxyethyl)-4-hydroxybenzo[d]thiazol-2(3H)-one hydrochloride (WO2007027134, example 1, step d) (243 mg) in dry methanol with 3 Å molecular sieves at room temperature under nitrogen and stirred for 5 minutes. The mixture was cooled to 0° C. and sodium triacetoxyborohydride (131 mg) was added. The reaction mixture was stirred, warming to room temperature overnight. The mixture was filtered and evaporated. Purification was by preparative HPLC (Phenomenex Gemini®, Gradient: 10-40% acetonitrile in 0.1% aqueous formic acid). The fractions containing product were combined and freeze-dried to afford the titled compound as a white solid. Yield 0.032 g.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:12][C:9]1[CH:10]=[CH:11][C:2]([Br:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(O)ccc1Br
Solvent: c1ccncc1
Product: COC(=O)c1cc(OC(C)=O)ccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl 2-bromo-5-hydroxybenzoate (20 g, 87 mmol) in pyridine (100 mL) was added acetic anhydride (10.2 g, 100 mmol) at 0° C. The mixture was stirred at ambient temperature for 16 hours, concentrated, and ethyl acetate was added. The mixture was washed with saturated NH4Cl(aq) to afford the crude title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.79 (d, J=8.7 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.30 (dd, J=8.7, 2.8 Hz, 1H), 3.86 (s, 3H), and 2.28 (s, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:34])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[O:32][CH3:33])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([CH:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)=[O:34])[CH:24]=2)=[C:26]([O:32][CH3:33])[CH:27]=1
Reactant: COc1cc(F)ccc1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Agent: [Pd]
Solvent: CO
Product: COc1cc(F)ccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
4-[6-(4-Fluoro-2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XIX) (0.42 g, 0.9 mmol) was dissolved in methanol (20 ml) and 10% Pd/C (0.2 g) was added under an atmosphere of nitrogen. The reaction was stirred at room temperature under hydrogen balloon pressure for 18 hours. The catalyst was removed from the reaction mixture by filtration through a celite bed and the filtrate was evaporated to dryness. Then the crude product was triturated with dry diethyl ether (5 ml) and the solid was filtered off to obtain piperidine-4-carboxylic acid [6-(4-fluoro-2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #10A,) (0.22 g, 76%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5][CH:4]=[C:3]1[C:21]([OH:23])=[O:22].C(Cl)(=O)C(Cl)=O.O[C:31]1[N:35]([CH2:36][CH3:37])[N:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CN(C)C=O>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:5][CH:4]=[C:3]1[C:21]([O:23][C:31]1[N:35]([CH2:36][CH3:37])[N:34]=[CH:33][CH:32]=1)=[O:22]
Reactant: O=C(O)c1cnc(-c2ccccc2)n(Cc2ccccc2)c1=O
Reactant: CCn1nccc1O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1nccc1OC(=O)c1cnc(-c2ccccc2)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,6-dihydro-6-oxo-2-phenyl-1-(phenylmethyl)-5-pyrimidinecarboxylic acid (i.e. the product from Example 2, Step C) (1.20 g, 3.92 mmol) in dichloromethane (30 mL) was added oxalyl chloride (998 mg, 7.84 mmol) at 0° C. followed by a catalytic amount (4-drops) of N,N-dimethylformamide. The reaction mixture was allowed to warm to room temperature and stir for 1 h. The reaction mixture was then concentrated under reduced pressure. To the resulting residue was added dichloromethane (30 mL) and 5-hydroxy-1-ethyl-1H-pyrazole, (572 mg, 4.7 mmol), followed by triethylamine (1.18 g, 11.8 mmol), and the reaction mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 70% ethyl acetate in hexanes to afford the title product as a white solid (700 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[CH3:27][C:28]1[CH:29]=[C:30]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=2)=[S:38])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[S:12][C:13]([S:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)=[C:14]([N+:16]([O-])=O)[CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[C:34]([O:36][CH2:37][C:38]([Cl:41])([Cl:40])[Cl:39])=[O:35]>ClCCl>[Cl:39][C:38]([Cl:41])([Cl:40])[CH2:37][O:36][C:34](=[O:35])[NH:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][C:13]2[S:12][C:11]([C:9](=[O:10])[NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[CH:15][C:14]=2[NH2:16])=[CH:21][CH:22]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(Sc2sc(C(=O)Nc3cccc(Br)c3)cc2[N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1cc(C(=O)Nc2cccc(Br)c2)sc1Sc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reaction time: 0.5 h

Procedure:
To the product from Example 356C dissolved in dichloromethane was added pyridine followed by the dropwise addition of 2,2,2-trichloroethyl chloroformate. The resultant solution was stirred for 4 hours and then concentrated under vacuum. The mixture was then poured into water, the pH of the solution adjusted to 5 with 1N aqueous hydrochloric acid, the resultant solution stirred for 30 minutes and the resultant solid collected and dried followed by reduction of the nitro group according to the procedure described in Example 356E to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[C:12]([C:17]([NH:19]C(C)(C)C)=O)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[C:12]([C:17]#[N:19])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)NC(=O)c1ncccc1CCc1ccc(Cl)c(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ncccc1CCc1ccc(Cl)c(Cl)c1
Yield: 91.6 %

Procedure:
A solution of 3-[2-(3,4-dichlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide (37.8 g, 0.107 mole) in 120 mL (197.4 g, 1.29 mole) of phosphorous oxychloride is heated at 110° C. for 4.5 hours. Completion of the reaction is determined by thin-layer chromotography. The reaction is quenched with ice and H2O and the pH of the solution is brought to 8 by the addition of a saturated solution of potassium carbonate. The product is extracted into ethylacetate. The solution is concentrated to a solid residue which upon recrystallization from diethyl ether/ethyl acetate provides the desired product, (27.1 g, 0.098 mole), in 91.6% yield.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8](C(O)=O)[C:7](=[O:13])[NH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2].C>C(O)(C)C>[C:1]([C:4]1[CH:12]=[CH:8][C:7](=[O:13])[NH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)c(=O)[nH]c1C
Solvent: CC(C)O
Product: CC(=O)c1ccc(=O)[nH]c1C
Temperature: 25 °C

Procedure:
A 10 g portion of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid was heated neat in a bath of a boiling mixture of diphenyl and diphenyl ether for 40 mixtures and the mixture allowed to cool to room temperature. The reaction mixture was dissolved in hot isopropyl alcohol, treated with decolorizing charcoal and filtered, and the filtrate allowed to stand at room temperature for several hours. The separated product was collected and dried at 90°-95° C. to yield 4.3 g of 5-acetyl-6-methyl-2-(1H)-pyridinone, m.p. 193°-195° C.
Reaction SMILES: N#N.C([O:7][C:8](=[O:22])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2([CH3:21])OCC[O:17]2)[CH:11]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[C:16]([C:12]1[CH:11]=[C:10]([CH2:9][C:8]([OH:22])=[O:7])[CH:15]=[CH:14][CH:13]=1)(=[O:17])[CH3:21]
Reactant: CC(C)(C)OC(=O)Cc1cccc(C2(C)OCCO2)c1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cccc(CC(=O)O)c1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-acetic acid tert-butyl ester (268 mg, 0.96 mmol) in TFA (3.89 mL) was stirred for 45 min at rt. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (25 mL) and 1N NaOH (10 mL). The layers were separated and the aq. layer was acidified with 1N HCl and extracted twice with CH2Cl2 (25 mL). The combined org. layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=0.73 min.
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[C@H:2]([C:12]([O:14]N1C(=O)CCC1=O)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.[NH2:29][C@H:30](C(O)=O)[CH2:31][CH2:32][C:33](=[O:35])[OH:34].[CH3:39][N:40]1[C@@H:57]2[CH2:58][C:45]3[CH:46]=[CH:47][C:48]([O:59][CH3:60])=[C:49]4[O:50][C@H:51]5[C:52]([CH2:54][CH2:55][C@@H:56]2[C@:43]5([C:44]=34)[CH2:42][CH2:41]1)=[O:53]>>[CH2:31]([C@H:30]([NH2:29])[C:22]([NH:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5]([OH:6])=[O:11])=[O:24])[CH2:32][C:33]([OH:35])=[O:34].[CH3:39][N:40]1[C@@H:57]2[CH2:58][C:45]3[CH:46]=[CH:47][C:48]([O:59][CH3:60])=[C:49]4[O:50][C@H:51]5[C:52]([CH2:54][CH2:55][C@@H:56]2[C@:43]5([C:44]=34)[CH2:42][CH2:41]1)=[O:53]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Glu-Glu-Hydrocodone was prepared by a similar method to Example 6 except the amino acid starting material was Boc-Glu(OtBu)-OSu and the conjugate starting material was Glu-Hydrocodone.