Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)=[O:3].[Cl:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[N:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]([O:21][CH2:1][C:2]([C:4]2[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][CH:5]=2)=[O:3])[CH:18]=[N:19][CH:20]=1
Reactant: Oc1cncc(Cl)c1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1cncc(Cl)c1)c1cccc([N+](=O)[O-])c1
Yield: 68.3 %

Procedure:
2-Fluoro-5-nitroacetophenone (3.6 g, 20 mmol, described by Cooper, et. al. J. Med. Chem. 33:1246-1252 (1990)) and 5-chloro-3-pyridinol (3.2 g, 25 mmol) were dissolved in acetone (20 mL). After addition of solid K2CO3 (3.5 g, 26 mmol), the reaction mixture was heated to reflux for 4 hr. The reaction mixture was cooled and acetone was removed under reduced pressure. The residue was suspended in deionized water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic portions were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a brown oil which was partially purified by column chromatography (silica gel, 4:1 hexanes:ethyl acetate) to provide 4 g of 2-(5-chloro-3-pyridyloxy)-5-nitro-1-phenylethanone. This material was dissolved in ethanol (40 mL) and acetic acid (5.3 mL, 93 mmol) to which iron powder (300 mesh, 2.6 g, 46.5 mmol) was added. The reaction mixture was heated to reflux for two days. After removal of excess iron (with a magnetic stir-bar retriever), the reaction mixture was poured into 300 mL of deionized water and extracted with ethyl acetate (3×100 mL). The combined organic portions were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a brown oil which was purified by column chromatography (silica gel, 4:1 hexanes:ethyl acetate). The product 5′-amino-2′-(5-chloro-3-pyridyloxy)-1-phenylethanone was obtained as a yellow oil (1.03g).
Reaction SMILES: O=[C:2]([CH3:24])[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:12][CH:11]=1)[C:4](OCC)=[O:5].C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31]>CCO>[NH2:32][C:30]1[N:31]=[C:4]([OH:5])[C:3]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:12][CH:11]=2)=[C:2]([CH3:24])[N:29]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(Cc1ccc(COC2CCCCO2)cc1)C(C)=O
Agent: O=C(O)O
Solvent: CCO
Product: Cc1nc(N)nc(O)c1Cc1ccc(COC2CCCCO2)cc1

Procedure:
A mixture of the product from step (i) (15.66 g) and guanidine carbonate (8.7 g) in EtOH (150 ml) was heated under reflux for 48 h. The mixture was cooled, the solvent removed under reduced pressure and the residue triturated with water. The solid was filtered, washed with water then diethylether and dried to afford the subtitle compound, 11.58 g.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[N:10]([CH:17]1[CH2:22][CH2:21][N:20](CC3C=CC=CC=3)[CH2:19][CH2:18]1)[CH2:9]2.[H][H]>[OH-].[Pd+2].[OH-].CO>[CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[N:10]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH2:9]2
Reactant: [H][H]
Reactant: CN(C)CCOc1ccc2c(c1)CN(C1CCN(Cc3ccccc3)CC1)C(=O)N2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCOc1ccc2c(c1)CN(C1CCNCC1)C(=O)N2

Procedure:
A mixture of 0.9 g (0.0022 mol) of 3,4-dihydro-6-[2-(dimethylamino)ethoxy]-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone, 10 mL methanol, and 0.5 g palladium(II) hydroxide (Pearlman's catalyst) was hydrogenated until the uptake of hydrogen ended. The catalyst was filtered off, the filtrate was evaporated down in vacuo, and the residue remaining was used in the next step without any further purification. Yield: 0.6 g (86% of theoretical). IR (KBr): 1662 (C═O) cm−1; MS: M+=318.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([CH3:17])[CH3:16])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:19])[C:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:17])[CH3:16])[CH3:12]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Temperature: 110 °C
Yield: 57.5 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (7 g, 45 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (11.4 g, 58 mmol), K2CO3 (18.6 g, 135 mmol) and KI (0.97 g, 5.8 mmol) were mixed in DMF (20 mL). Then the reaction mixture was heated at 110° C. for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound (7 g)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[C:47]1([N:53]=[C:54]=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>ClC(Cl)C>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:54]([NH:53][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:55])=[O:43]
Reactant: O=C=Nc1ccccc1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2ccccc2)s1
Reaction time: 4 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (5.0 g) was dissolved in dichloroethane (80 ml). Phenyl isocyanate (0.807 ml) and triethylamine (2.8 ml) were added at room temperature, and the mixture was stirred for 4 hours. Then, the reaction mixture was washed with water and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 2.1 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-N'-phenylurea.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OCC)ccn1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 17 h
Yield: 75 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (16 mg, 0.045 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 17 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:8) to furnish IV as a colourless oil (12 mg, 75%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]1([C:52]2[S:53][CH:54]=[C:55]([C:57](O)=[O:58])[N:56]=2)[CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(CC)CC)C>CN(C=O)C>[CH:47]1([C:52]2[S:53][CH:54]=[C:55]([C:57]([N:28]3[CH2:29][C:30]4([CH2:35][CH2:34][N:33]([CH2:36][C:37]5[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=5)[CH2:32][CH2:31]4)[O:25][CH2:26][CH2:27]3)=[O:58])[N:56]=2)[CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: O=C(O)c1csc(C2CCCC2)n1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1csc(C2CCCC2)n1)N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1
Reaction time: 0.5 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.33 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.21 g), 2-cyclopentylthiazole-4-carboxylic acid (example 59, step d) (0.13 g) and triethylamine (0.38 mL) in DMF (7 mL) and the resulting yellow solution was stirred for 30 min. The mixture was partitioned between ethyl acetate and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.19 g.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:29]=[C:17]2[N:18]=[C:19]([NH2:28])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]2[N:15]=1>N1C=CC=CC=1>[CH3:13][C:14]1[CH:29]=[C:17]2[N:18]=[C:19]([NH:28][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]2[N:15]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccccc3)cc(-c3ccccc3)n2n1
Temperature: 25 °C

Procedure:
In a round-bottomed flask was a mixture of (1R,2R)-2-phenylcyclopropanecarbonyl chloride and cis (+/+,−/−)-2-phenylcyclopropanecarbonyl chloride (200 mg, 1.1 mmol) added in Pyridine (5 mL) to give a yellow suspension. 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 124 mg, 0.554 mmol) was added portionwise at 0° C. The temperature was slowly raised to room temperature. The reaction was quenched with saturated sodium bicarbonate and partitioned between ethyl acetate and water. The separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure (3×100 mL). The reaction mixture was filtered and purified by preparatory HPLC (70-80% MeCN/H2O gradient+0.01% TFA). Received 62 mg (30%) of yellow solid. Melting point (208.2-208.3° C.). 1H NMR (DMSO-d6) δ: 11.28 (s, 1H), 7.93-8.10 (m, 2H), 7.90 (s, 1H), 7.55-7.68 (m, 3H), 7.28-7.34 (m, 2H), 7.17-7.25 (m, 3H), 6.33 (s, 1H), 2.42-2.48 (m, 1H), 2.37 (s, 4H), 1.34-1.63 (m, 2H); [α]D20=−238° (c=1.058, MeOH). ESI-MS: m/z 369.0 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([Cl:19])[N:10]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21]>O>[CH3:8][C:9]1[N:10]=[C:11]([Cl:19])[C:12]([N+:16]([O-:18])=[O:17])=[C:13]([NH:23][CH:20]([CH3:22])[CH3:21])[N:14]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)N
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NC(C)C)n1
Reaction time: 4 h
Yield: 73.4 %

Procedure:
30 ml of triethylamine are added to 32.5 g (0.156 mol) of 2-methyl-4,6-dichloro-5-nitro-pyrimidine. At -18° C, 3.5 g of isopropylamine (0.16 mol) are added dropwise and the mixture is then stirred for 11/4 hours at this temperature. The mixture is subsequently poured on 4 liters of water, the precipitate is filtered off with suction, and washed 3 times with water. The crude product is dried at 50° C and 11 Torr for 16 hours, to yield 26.4 g of 2-methyl-4-chloro-5-nitro-isopropylamino-pyrimidine with a melting point of 69°-72° C. The pure substance (recrystallised from hexane) melts at 77°-79° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:16]([CH2:21][C@H:22]3[CH2:42][CH2:41][C:24]4([O:28][C@H:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C@@H:26]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:25]4)[CH2:23]3)[C:17]([O:19]C)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[OH-].[Na+].CO>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:16]([CH2:21][C@H:22]3[CH2:42][CH2:41][C:24]4([O:28][C@H:27]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C@@H:26]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:25]4)[CH2:23]3)[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1
Reactant: COC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of methyl 2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propionate (66.5 g), 4 M aqueous sodium hydroxide solution (66.5 mL), methanol (66.5 mL), and THF (133 mL) was stirred under heating and reflux for 30 minutes, and left to be cooled at room temperature, and the organic solvent was evaporated under reduced pressure. To the residue was added chloroform (500 mL), and concentrated hydrochloric acid (25 mL) was then added thereto under ice-cooling. The organic layer was washed with saturated brine (200 mL×2) and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to obtain 2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propionic acid (64.8 g) as an off-white amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][CH2:19][N:14]3[C@@H:13]3[CH2:20][CH2:21][NH:22][CH2:23][C@H:12]23)[CH:17]=1.Cl[CH2:25][CH2:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][CH2:19][N:14]3[C@@H:13]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][CH2:27][C:28]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)=[O:29])[CH2:23][C@H:12]23)[CH:17]=1
Reactant: Clc1ccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CC3)c(Cl)c1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC3)c1ccc(F)cc1
Yield: 37.2 %

Procedure:
The title compound (36 mg, 37%) was prepared by the method of Example 189 from (±)-cis-2-(2,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole (65.8 mg, 0.19 mmol), 4-chloro-4′-fluorobutyrophenone (50.0 mg, 0.25 mmol), KI (31.5 mg, 0.19 mmol), and K2CO3 (50.0 mg, 0.57 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.90-7.95 (m, 2 H), 7.37 (s, 1H), 7.16 (s, 2H), 7.03 (t, 2H, J=8.8 Hz), 6.91 (s, 1H), 6.85 (s, 1H), 3.49 (bt, 1H, J=8.0 Hz), 3.25-3.45 (m, 2H), 3.02-3.22 (m, 2H), 2.90-3.02 (m, 3H), 2.50-2.88 (m, 2H), 2.10-2.45 (m, 4H), 1.70-2.00 (m, 4H) ppm. MS (CI, NH3): 509 (base, M+H).
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[OH:33])[C:28]#[N:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[C:28]([C:27]1[CH:30]=[CH:31][C:32]([O:33][C:2]2[C:7]3[O:8][CH2:9][CH2:10][N:11]([CH:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)[C:6]=3[N:5]=[CH:4][N:3]=2)=[C:25]([F:24])[CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: CC(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)OC(=O)N1CCC(N2CCOc3c(Oc4ccc(C#N)cc4F)ncnc32)CC1
Temperature: 120 °C
Reaction time: 72 h
Yield: 7.8 %

Procedure:
To a solution of isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 20A (10.0 mg, 0.029 mmol) and 3-fluoro-4-hydroxybenzonitrile (12.07 mg, 0.088 mmol) in DMF (0.4 mL) was added K2CO3 (12.17 mg, 0.088 mmol). The reaction mixture was stirred in a sealed vial for 3 days at 120° C. The reaction mixture was cooled to RT. The reaction mixture was diluted with MeOH, filtered and purified by reverse phase HPLC (H2O/CH3CN) to give isopropyl 4-(4-(4-cyano-2-fluorophenoxy)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate (1.0 mg, 2.265 μmol, 7.72% yield) as Example 148 as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (d, J=6.05 Hz, 6 H) 1.55-1.79 (m, 4 H) 2.85-2.95 (m, 2 H) 3.44-3.54 (m, 2 H) 4.05-4.15 (m, 2 H) 4.24-4.35 (m, 2 H) 4.84-4.95 (m, 2 H) 7.29-7.40 (m, 1 H) 7.45-7.52 (m, 2 H) 7.88 (s, 1 H). LRMS (ESI): 442.5 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][OH:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H](COC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.1 %

Procedure:
To a stirred solution of 2.32 g (0.012 mol) of p-toluensulfonic acid and 0.95 g (0.012 mol) of pyridine in 250 mL of dichloromethane, 25.0 g (0.12 mol) of Intermediate 1 was added. Then, 24.22 g (0.29 mol) of dihydropyran was added dropwise and the resulting mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was redissolved in ethyl acetate (350 mL). The organic phase was washed with water (2×250 mL) and dried over sodium sulphate. The solvent was evaporated under vacuum and 49.00 g of a pale yellow oil was obtained. The oil was not purified and used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:37])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:24][CH2:25][CH:26]([NH2:29])[CH2:27][CH2:28]3)=[O:22])[C:9]=2[CH3:37])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCC(N)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 94 %

Procedure:
tert-Butyl N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}piperidin-4-yl)carbamate (194 mg) was stirred in dichloromethane (7 mL) and trifluoroacetic acid (3 mL) for 4 h. The reaction was concentrated in vacuo and dissolved in ethyl acetate. The solution was washed with 3.8 N NaOH and brine. The organic layer was dried with magnesium sulfate. The reaction was concentrated in vacuo to yield 0.15 g (94%) of desired product. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31-1.52 (m, 2H) 1.83-2.02 (m, 2H) 2.14-2.26 (m, 3H) 2.84-3.07 (m, 2H) 3.11-3.33 (m, 1H) 4.31 (d, J=13.47 Hz, 1H) 4.66 (d, J=13.19 Hz, 1H) 7.07 (d, J=8.38 Hz, 2H) 7.14-7.20 (m, 1H) 7.21-7.34 (m, 3H) 7.44 (d, J=1.98 Hz, 1H); [M+H]+ 463.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[N:34]=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[N:34]=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)n1

Procedure:
Example 29 was prepared from bis(4-fluorophenyl)acetic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.4 Hz), 7.99 (m, 1H), 7.84 (s, 1H), 7.63 (t, 1H, J=8.0 Hz), 7.39–7.32 (m, 4H), 7.03–6.97 (m, 4H), 6.87 (d, 1H, J=7.6 Hz), 4.91 (s, 1H), 3.39 (dd, 2H, J=5.2, 11.2 Hz), 3.07 (d, 2H, J=11.6 Hz), 2.62 (m, 1H), 2.55 (t, 2H, J=6.4 Hz), 2.34 (m, 1H), 2.16 (t, 2H, J=11.2 Hz), 1.93–1.73 (m, 6H), 1.16 (d, 6H, J=6.8 Hz); ESMS m/e: 535.4 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:20]([O:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:21])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCCc1ccccc1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)OCCc2ccccc2)N(c2nnc(C(C)(C)C)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and themometer. The solution is cooled to a temperature of about 10° C. and phenethyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-phenethyloxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: O[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH:27]([CH3:29])[CH3:28])[CH:20]=1)[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][C:4]=1[CH3:18].[H][H]>[Pd]>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:2][C:3]2[C:4]([CH3:18])=[CH:5][C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:7][C:8]=2[CH3:9])=[CH:20][C:21]=1[CH:27]([CH3:29])[CH3:28]
Reactant: [H][H]
Reactant: COc1ccc(C(O)c2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1C(C)C
Agent: [Pd]
Product: COc1ccc(Cc2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1C(C)C

Procedure:
730 mg (1.66 mmol) of tert-butyl 4-[hydroxy(4-methoxy-3-isopropylphenyl)methyl]-3,5-dimethylphenylcarbamate (Example V) are hydrogenated with 700 mg of Pd/C (10%) and with 1 bar of hydrogen at RT for 4 hours. The mixture is filtered through kieselguhr, the solvent is removed in vacuo, and purification by chromatography results in 578 mg (91%) of tert-butyl 4-(4-methoxy-3-isopropylbenzyl)-3,5-dimethylphenylcarbamate.