Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([N+:18]([O-])=O)[CH:10]=2)[CH:2]([CH3:4])[CH3:3].CO.[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([N:5]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([NH2:18])[CH:10]=2)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)Cn1c2c(c3cc(N)ccc31)CCCC2
Yield: 92.2 %

Procedure:
A solution of the compound obtained in Step 1 (290 mg, 1.06 mmol) and 10% palladium on carbon (50% wet, 10 mg, 0.09 mmol) in a mixed solvent of methanol (4 mL) and ethyl acetate (4 mL) was stirred at room temperature for 14 hr under 1 atm of hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 9-isobutyl-2,3,4,9-tetrahydro-1H-carbazol-6-amine (237 mg, 0.977 mmol, 92%) as a brown oil.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][C:36](=[NH:38])[NH2:37])=[CH:30][CH:29]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:7][C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][C:36](=[NH:37])[NH2:38])=[CH:30][CH:29]=1)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CC(=O)O
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(C)CC(=O)Oc1ccc(C=CC(=N)N)cc1
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Into 10 ml of dried pyridine, was dissolved 1.0 g of isovaleric acid. To the solution, while being cooled in ice, was added 2.5 g of DCC. After 30 minutes of stirring, 2.6 g of 4-(β-amidinoethenyl)phenol methanesulfonate was added and the mixture was stirred overnight at room temperature. The reaction mixture was removed of precipitated DCU by filtration and the DCU was washed with pyridine. Ethyl ether was added to the combined filtrate to precipitate a white solid substance which was collected by filtration, washed with ethyl ether, and recrystallized from ethanol to yield 1.7 g of colorless flaky crystals of 4-(β-amidinoethenyl)phenyl isovalerate methanesulfonate.
Reaction SMILES: CC1(C)COC(C([C@@H]2[C@]3(C)[C@H](C4[C@H](CC3)[C@]3(C)C(C[C@@H](OC(OC)=O)C[C@@H]3O)=CC=4)CC2)C)[O:4][CH2:3]1.[CH3:36][O:37][C:38]([O:40][C@@H:41]1[C@@:59]2([CH3:60])[C:45](=[CH:46][CH:47]=[C:48]3[C@@H:58]2[CH2:57][CH2:56][C@@:55]2([CH3:61])[C@H:49]3[CH2:50][CH2:51][C@@H:52]2[CH2:53][CH3:54])[CH2:44][C@@H:43]([O:62]C(OC)=O)[CH2:42]1)=[O:39]>>[OH:62][C@H:43]1[CH2:42][C@H:41]([O:40][C:38]([O:37][CH3:36])=[O:39])[C@@:59]2([CH3:60])[C:45](=[CH:46][CH:47]=[C:48]3[C@@H:58]2[CH2:57][CH2:56][C@@:55]2([CH3:61])[C@H:49]3[CH2:50][CH2:51][C@@H:52]2[CH:53]([CH:3]=[O:4])[CH3:54])[CH2:44]1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O)C1
Reactant: CC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)OC)C[C@H](OC(=O)OC)[C@]4(C)[C@H]3CC[C@]12C
Product: COC(=O)O[C@H]1C[C@H](O)CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@]21C

Procedure:
The reaction and workup procedures of Example 156 were repeated except that 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl )-3β-(methoxycarbonyl)oxypregna-5,7-dien-1α-ol was used in lieu of 100 mg of 20-(5,5-dimethoxycarbonyl)oxypregna-1,3-dioxan-2-yl)-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene to give 55 mg of 3β-hydroxy-1α-(methoxycarbonyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].O=C1CCC(=O)N1[O:21][C:22](=O)[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:47]=[CH:46][C:30]2[CH:31]([CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[C:32]3[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=3[CH2:34][CH2:35][C:29]=2[CH:28]=1.Cl>O.C1COCC1>[CH3:45][N:43]([CH3:44])[CH2:42][CH2:41][CH2:40][CH:31]1[C:30]2[CH:46]=[CH:47][C:27]([O:26][CH2:25][CH2:24][CH2:23][C:22]([NH:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=3)=[O:21])=[CH:28][C:29]=2[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]1=2
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)ON3C(=O)CCC3=O)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)NCc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
A mixture of 32 mg (0.212 mmol) of 4-(aminomethyl)benzoic acid in 2 ml of H2O and 4 ml of THF was treated with approximately 0.1 ml of 2 N NaOH such that the pH of the mixture was about 9. This was then treated with a solution of 100 mg (0.209 mmol) of the TCA NHS ester 9 in 4.5 ml of THF. The pH was adjusted to about 8.5-9.0 with 2 N NaOH and the reaction was stirred at room temperature for 15 minutes. The reaction was neutralized to pH 6 with 2 N HCl, then extracted twice with CH2Cl2. The CH2Cl2 portions were combined, dried over anhydrous Na2SO4 and concentrated in vacuo to give 87 mg (81%) of the acid 15 as a pale yellow oil. This was used in the next step without further purification.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][CH:31]=[N:32]2)(=[O:14])=[O:13])[C:9]#[N:10])(C)(C)C.C1(C)C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C@H:8]([C:9]#[N:10])[CH2:7][C:6]([OH:37])=[O:5])(=[O:14])=[O:13])=[C:16]([O:24][CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[N:32]3)[CH:17]=1)(=[O:23])[NH2:22]
Reactant: CC(C)(C)OC(=O)C[C@@H](C#N)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: N#C[C@H](CC(=O)O)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Yield: 106.7 %

Procedure:
A solution of (S)-3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-3-cyano-propionic acid tert-butyl ester (0.13 g, 0.20 mmol) in TFA (2 mL) and CH2Cl2 (20 mL) was stirred for 9 h. Toluene (50 mL) was added and the solvents were removed under vacuum. The residue was lyophilized to yield 100 mg (99%) of (S)-3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-3-cyano-propionic acid as a pale yellow solid. MS m/z 469.2 (M+1).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](C2C=CC=CC=2B(O)O)=[CH:13][CH:12]=1>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1-c1ccc(Cl)cc1
Reactant: OCc1ccccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: OCc1ccccc1-c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
A mixture of 2-iodobenzyl alcohol (11.0 g), 4-chlorophenylbenzeneboronic acid (8.5 g), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (800 mg) in Na2CO3 (2M solution, 94 mL) and dioxane (300 mL) was heated to 80° C. for 24 hours. The mixture was cooled, the layers were separated, and the organic layer was condensed. The resulting residue was purified by silica gel chromatography eluting with 20% ethyl acetate in hexanes to give the desired product.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][CH2:16][C:17]1([OH:20])[CH2:19][CH2:18]1.C(O[K])(C)(C)C.O>CN(C=O)C>[Cl:12][C:8]1[C:9]([Cl:11])=[N:10][C:2]([O:13][CH2:14][CH2:15][CH2:16][C:17]2([OH:20])[CH2:19][CH2:18]2)=[C:3]([CH:7]=1)[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc(Cl)c(Cl)nc1Cl
Reactant: OCCCC1(O)CC1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Cl)c(Cl)nc1OCCCC1(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A mixture of compound 2,5,6-trichloronicotinamide (0.6 g, 2.7 mmol), 1-(3-hydroxypropyl)cyclopropanol (370 mg, 3.2 mmol) and tert-BuOK (363 mg, 3.2 mmol) in DMF was stirred at room temperature overnight and the reaction mixture was then poured into cold water, the mixture was extracted twice with ethyl acetate, the combined organic layers were washed with brine twice, dried over Na2SO4 and concentrated, the residue was purified by column chromatography (silica gel, Petroleum ether: EtOAc=1:0 to 5:1) to give the 5,6-dichloro-2-(3-(1-hydroxycyclopropyl)propoxy)nicotinamide (0.72 g, 73%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.65 (s, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 5.48 (s, 1H), 4.82 (t, 2H, J=6.4 Hz), 2.36 (m, 2H), 1.97 (m, 2H), 0.94 (t, 2H), 0.73 (t, 2H).
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH:30]1([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH:20]3[CH2:21][CH2:22][N:17]([C:15]([C:12]4[CH:13]=[N:14][C:9]([N:2]5[CH2:3][CH2:4][CH2:5][S:1]5(=[O:7])=[O:6])=[CH:10][CH:11]=4)=[O:16])[CH2:18][CH2:19]3)=[CH:25][CH:26]=2)[CH2:31][CH2:32]1
Reactant: O=S1(=O)CCCN1
Reactant: O=C(c1ccc(Br)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Product: O=C(c1ccc(N2CCCS2(=O)=O)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Yield: 60.5 %

Procedure:
Using isothiazolidine 1,1-dioxide (230 mg) and (6-bromopyridin-3-yl)[4-(4-cyclopropylphenoxy)piperidin-1-yl]methanone (635 mg) described in Preparation Example 192 and by the reaction and treatment in the same manner as in Example 1, the title compound (423 mg) was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:15])[C:10](=[NH:14])[O:11]CC)[CH:6]=[CH:7][CH:8]=1.[O:16]1CCC[CH2:17]1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[O:15][C:17](=[O:16])[NH:11][C:10]2=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1cccc(Cl)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2cccc(Cl)c2)O1

Procedure:
By the procedure of Example 3, ethyl 1-(3-chlorophenyl)-1-hydroxymethanecarboximidate hydrochloride (9 g., 38 moles) in 250 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(3-chlorophenyl)oxazolidine-2,4-dione (4.5 g., 56%, m.p. 142°-144° C.)
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=3)=[N:17]2)=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:29])[CH:3]=1.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])=[CH:24][CH:23]=3)=[N:17]2)=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:29])[CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C#Cc1ccc(-c2nn(-c3cc(CNC(=O)C(C)(C)C)c(F)cc3Cl)c(=O)[nH]2)cc1
Yield: 54.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 using N-(4-chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-90, 0.100 g, 0.189 mmol), 3,3-dimethylbut-1-yne (0.031 g, 0.378 mmol), TBAF (0.178 g, 0.567 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (3.0 mL) to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.10 (s, 9H), 1.30 (s, 9H), 4.30 (d, J=9.0 Hz, 2H), 7.43-7.50 (m, 3H), 7.65 (d, J=9.3 Hz, 1H), 7.78 (d, J=8.1 Hz, 2H), 8.14 (br s, 1H), 12.60 (br s, 1H); MS (m/z): 483.29 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])O)[CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([NH2:37])=[O:36].O>CN(C=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:22][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[N:8]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:10])=[O:11])[CH2:34][C:35]([NH2:37])=[O:36]
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(C)cc2C(O)c2ccccc2Cl)cc1OC
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(CC(N)=O)c2ccc(C)cc2Cc2ccccc2Cl)cc1OC
Reaction time: 18 h
Yield: 78 %

Procedure:
To 0.47 g of N-{4-methyl-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenzenesulfonamide dissolved in 5.7 ml of DMF is added, at 0° C., 0.048 g of sodium hydride. After 1 hour at this temperature, 0.166 g of 2-bromoacetamide is introduced and the mixture is left for 18 hours at room temperature. The medium is poured into water and then extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate mixture to give 0.4 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[ClH:38].O1CCOCC1>C(Cl)Cl>[ClH:1].[ClH:38].[ClH:1].[Cl:1][C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([C:26]2([NH2:30])[CH2:29][CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 90.6 %

Procedure:
tert-Butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (36.4 mg, 0.0708 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 15.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (33.6 mg, 90.6%) as yellow solid. 1H NMR (DMSO-d6) 400 MHz δ: 8.72 (br s, 2H), 8.68 (s, 1H), 8.16 (dd, J=4.8, 1.8 Hz, 1H), 7.82 (dd, J=7.8, 1.8 Hz, 1H), 7.61-7.55 (m, 2H), 7.42-7.27 (m, 4H), 7.13-7.07 (m, 1H), 6.98 (dd, J=7.8, 1.8 Hz, 1H), 6.81 (dd, J=7.8, 4.8 Hz, 1H), 4.27 (br s, 3H), 2.64-2.43 (m, 4H), 2.26-2.12 (m, 1H), 1.89-1.74 (m, 1H); LCMS: 414 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:18])[CH:3]=1.C(OC1C=CC(NC2N=CN=C(OC3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.Cl[C:72](=[O:79])[CH2:73][C:74]([O:76][CH2:77][CH3:78])=[O:75]>CN(C=O)C.CCOC(C)=O>[C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:72](=[O:79])[CH2:73][C:74]([O:76][CH2:77][CH3:78])=[O:75])=[CH:3][C:4]=2[F:18])[CH:12]=[CH:11][N:10]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)picolinamide (Compound B′ of Example 24, 1.0 g, 4.0 mmol) in DMF (10.0 mL) were added DIEA (2.0 mL) and ethyl 3-chloro-3-oxopropanoate (Aldrich, 0.75 mL, 6.0 mmol). The mixture was stirred at room temperature for 12 h and more ethyl 3-chloro-3-oxopropanoate (0.20 mL, 1.6 mmol) was added. The mixture was stirred for 2 h and was then diluted with EtOAc (200 mL). It was washed with H2O and brine and then dried over MgSO4. After filtration and concentration, the residue was triturated with DCM and filtered to give ethyl 3-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate (900 mg, 62% yield). MS (ESI+) m/z 362.28 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].Cl[CH2:12][CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH:4][CH2:12][CH:13]=[O:14]
Reactant: COc1ccc(C)c(N)c1
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(C)c(NCC=O)c1
Temperature: 150 °C

Procedure:
2-Methyl-5-methoxyaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer. thermometer and reflux condenser. The reaction mixture is heated to about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-methoxyanilino)acetaldehyde.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:26])[CH2:17][C:18]2[C:23]([Br:24])=[CH:22][N:21]=[C:20]([Cl:25])[CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([CH:16]([OH:26])[CH2:17][C:18]2[C:23]([Br:24])=[CH:22][N:21]=[C:20]([Cl:25])[CH:19]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)Cc2cc(Cl)ncc2Br)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (240 mg) is added to an ice-cooled solution of 4-[2-(5-bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylic acid tert-butyl ester (1.65 g) in a mixture of tetrahydrofuran (40 mL) and water (10 mL). The resulting mixture stirred for 0.5 h. 2 N Citric acid is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with aqueous NaHCO3 solution and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 65:35) to give the title compound. LC (method 5): tR=1.48 min; Mass spectrum (ESI+): m/z=419, 421 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])[CH3:17].CNC>>[CH2:1]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]([OH:9])([CH2:17][C:16](=[O:18])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)c1ccccn1
Reactant: CCCCN1C(=O)C(=O)c2ccccc21
Agent: CNC
Product: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a clean dry flask equipped with a stir bar was added the N-butyl isatin (0.4 grams, 1.97 mmol, 0.3 M in Methanol). 2-acetyl pyridine (0.44 mL, 3.94 mmol, purchased from Fisher Scientific) was then added to the stirring solution followed by 49 μL of dimethyl amine (40% by weight in water, purchased from Fisher Scientific). The stirring solution was stirred overnight at room temperature. The next day the solution was heated to 60° C. for 5 minutes. The solution was then concentrated and purified on a silica gel column using hexanes/ethyl acetate (2:1) to afford 0.513 grams, 80% yield. 1H-NMR δ 8.69 (d, 1H), 8.14 (d, 1H), 7.92 (t, 1H), 7.56 (m, 1H) 7.30 (m, 2H), 7.06 (t, 1H), 6.87 (d, 2H), 3.81 (d, 1H), 3.69 (m, 2H), 3.52 (d, 1H), 1.71 (m, 2H), 1.43 (m, 2H), 0.97 (t, 3H). Calculated mass for C19H20N2O3, 324.37. Observed 325.0 (M+1), 347.2 (M+Na).
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21][C:22]#[N:23])[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:26][CH2:27][CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2].[Cl-].[NH4+].[N-:32]=[N+:33]=[N-:34].[Na+].Cl>CN(C)C=O>[C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21][C:22]4[NH:34][N:33]=[N:32][N:23]=4)[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:26][CH2:27][CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccn3c(=O)c(CC#N)cnc23)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2cccn3c(=O)c(Cc4nnn[nH]4)cnc23)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 47.8 %

Procedure:
A mixture of 1.04 g (2.65 mmoles) of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-cyanomethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 1.00 g (18.69 mmoles) of ammonium chloride, 1.21 g (18.61 mmoles) of sodium azide and 30 ml of dimethylformamide was heated at 100°-110° C. for 8 hours with stirring. After cooling, the resulting reaction solution was poured into ice water and then acidified with dilute hydrochloric acid. The precipitate so formed was collected by filtration and recrystallized from dimethylformamide to obtain 0.55 g (48% yield) of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-[(1H-tetrazol-5-yl)methyl]-4H-pyrido[1,2-a]pyrimidin-4-one in the form of pale-yellow crystals. These crystals had a melting point of 250°-253° C. (dec.).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([OH:28])=[CH:20][CH:19]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([OH:28])=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Nc1ccc(O)c2ccccc12
Product: O=C(Nc1ccc(O)c2ccccc12)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-1-naphtol (Aldrich), the title compound was obtained as a grey solid.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[OH:21][CH2:22][C:23]1[C:28]([CH3:29])=[C:27]([OH:30])[C:26]([CH3:31])=[CH:25][N:24]=1.[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[O:19]1[C:20]2[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([OH:5])([C:7]([F:9])([F:10])[F:8])[CH2:6][N:24]3[CH:25]=[C:26]([CH3:31])[C:27](=[O:30])[C:28]([CH3:29])=[C:23]3[CH2:22][OH:21])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: Cc1cnc(CO)c(C)c1O
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cn(CC(O)(CC(C)(C)c2cccc3c2OCC3)C(F)(F)F)c(CO)c(C)c1=O
Temperature: 85 °C
Yield: 22.6 %

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran (30.0 mg) and 2-hydroxymethyl-3,5-dimethylpyridin-4-ol (32.2 mg) in anhydrous ethanol (0.25 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 39.0 μL). After heating at 85° C. for 18 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 4% to 7% methanol-methylene chloride) to give the title compound as a white solid (10.4 mg), m.p. 160° C.-162° C.