Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH2:18]Br)[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:18][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:8]([OH:9])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: ONCc1ccccc1
Reactant: BrCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: ON(Cc1ccccc1)Cc1ccc(CN(O)Cc2ccccc2)cc1

Procedure:
The procdure of Example 1 is repeated using 5.59 g of benzylhydroxylamine, 5.99 g of p-xylylene dibromide and 6.0 g of anhydrous sodium carbonate. The reaction product is recrystallized from acetonitrile to give the product as a white solid; m.p. 160°-163° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]4C(C#N)=CSC=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[N:55]1[CH:60]=[CH:59][CH:58]=[N:57]C=1C1C=CC(O)=CC=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:43]=[CH:44][C:45]([C:48]4[N:57]=[CH:58][CH:59]=[CH:60][N:55]=4)=[CH:46][CH:47]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: Oc1ccc(-c2ncccn2)cc1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(-c4ncccn4)cc3)s1)CC2

Procedure:
The title compound 81 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 81A: 1H NMR (DMSO-d6): δ 8.83 (d, J=4.88 Hz, 2H), 8.32 (d, J=8.85 Hz, 2H), 8.03 (d, J=4.88 Hz, 1H), 7.79 (d, J=8.85 Hz, 1H), 7.67 (d, J=7.63 Hz, 1H), 7.34-7.49 (m, 5H), 7.04 (d, J=8.85 Hz, 2H), 4.84 (s, 2H), 4.07 (t, J=6.26 Hz, 2H), 3.72 (t, J=5.95 Hz, 2H), 3.18-3.12 (m, 2H), 3.03 (t, J=5.64 Hz, 2H), 2.01-2.07 (m, 2H). ESI (+)/MS: 649 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:33])[CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]([CH2:25][C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])[O:23][CH:24]=3)=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.C(OCC)C.[Pd]>[OH:33][C@H:8]([C:5]1[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=1)[CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([CH2:25][C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[O:23][CH:24]=2)=[CH:18][CH:19]=1
Reactant: O=C(Cc1nc(-c2ccc(OCCNC[C@H](O)c3ccc(Cl)nc3)cc2)co1)N1CCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: O=C(Cc1nc(-c2ccc(OCCNC[C@H](O)c3cccnc3)cc2)co1)N1CCCC1
Reaction time: 8 h
Yield: 60 %

Procedure:
In a nitrogen-purged, round-bottomed flask, (R)-2-[4-(4-{2-[2-(6-chloro-pyridin-3-yl)-2-hydroxy-ethylamino]-ethoxy}-phenyl)-oxazol-2-yl]-1-pyrrolidin-1-yl-ethanone 1-1A (200 mg, 0.42 mmol) was dissolved in methanol (15 ml). 10% Pd/C (160 mg, 80 wt %), and ammonium formate (321 mg, 5.1 mmol) were then added sequentially. The reaction mixture was stirred overnight, and was then filtered through a pad of diatomaceous earth, and the filter cake rinsed with ethyl acetate. The filtrate was concentrated to a white solid, which was taken up in ethyl acetate and saturated aqueous sodium carbonate, and extracted. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a crude solid. This material was suspended in diethylether and isolated by vacuum filtration to afford a crystalline solid 1-1B (110 mg, 59% yield). This material was then converted to the corresponding hydrochloride salt. Analytical data for the HCl salt: LRMS ([M+H]+): 437.4. 1H NMR: (400 MHz, CD3OD): δ1.91 (m, 2H), 2.02 (m, 2H), 3.37-3.29 (m, 2H), 3.45 (m, 2H), 3.54-3.63 (m, 5H), 3.97 (s, 2H), 4.37 (t, 2H, J=4.8 Hz), 5.38 (dd, 1H, J=3.2,10.4 Hz), 7.07 (dd, 2H, J=2.8, 9.6 Hz), 7.69 (dd, 2H, J=1.8, 6.4 Hz), 8.14 (m, 2H), 8.75 (m, 1H), 8.86 (d, 1H, J=6.0 Hz), 8.99 (m, 1H). Preparation for 2-[4-(4-{2-[2(R)-Hydroxy-2-(6-methyl-pyridin-3-yl)-ethylamino]-ethoxy}-phenyl)-oxazol-2-yl]-N,N-dimethyl-acetamide (1-1C)
Reaction SMILES: I[C:2]1[N:3]([CH3:13])[CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=1.[CH3:14][C:15]1([CH3:31])[C:27]2[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2.C([O-])([O-])=O.[Na+].[Na+]>O.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:15]1([CH3:31])[C:16]2[CH:17]=[C:18]([C:2]3[N:3]([CH3:13])[CH:4]=[C:5]([C:7]4[S:8][C:9]([CH3:12])=[CH:10][CH:11]=4)[N:6]=3)[CH:19]=[CH:20][C:21]=2[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
Reactant: Cc1ccc(-c2cn(C)c(I)n2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cn(C)c(-c3ccc4c(c3)C(C)(C)c3ccccc3-4)n2)s1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 2-iodo-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 6 (1.26 g, 4.16 mmol), (9,9-dimethyl-9H-fluoren-2-yl)boronic acid (1.19 g, 5.00 mmol), Na2CO3 (2.20 g, 20.8 mmol) in H2O (10 mL) and DMF (40 mL) was degassed (N2 bubbling). Pd(PPh3)4 (120 mg, 0.10 mmol) was added and the mixture was heated to reflux for 2 h. The mixture was allowed to cool to room temperature and concentrated. The mixture was filtered through Celite washing with CH2Cl2 and the combined filtrate and washings were concentrated. The residue was taken up in CH2Cl2 and H2O and the organic phase was separated. The aqueous phase was re-extracted (CH2Cl2) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 5:95 then 10:90 then 12:88) to give 2-(9,9-dimethyl-9H-fluoren-2-yl)-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 9 (1.19 g, 76%) as a colourless solid. A portion of this material was further purified by, firstly, recrystallisation (EtOAc/hexanes) and, secondly, by sublimation (180° C., 10−6 mBar): m.p. 188-191° C. (DSC)1H NMR (CDCl3, 400 MHz) δ1.53 (s, 6H), 2.50 (d, J=0.6 Hz, 3H), 3.76 (s, 3H), 6.68-6.71 (m, 1H), 7.11 (s, 1H), 7.13-7.19 (m, 1H), 7.32-7.40 (m, 2H), 7.43-7.49 (m, 1H), 7.58 (dd, J 1.4, 8.0 Hz, 1H), 7.73-7.81 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ15.3, 27.1, 34.6, 47.0, 117.1, 119.8, 120.3, 122.1, 122.7, 123.6, 125.6, 127.0, 127.7, 137.8, 138.5, 139.9, 148.3, 153.9, 154.0; HRMS (EI) m/z 370.1490 C24H22N2S [M]+. requires 370.1498.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:9]=[C:8]([CH3:10])[N:7]([CH2:11][CH3:12])[N:6]=1)C.Cl>O>[CH2:11]([N:7]1[C:8]([CH3:10])=[N:9][C:5]([CH:4]=[O:3])=[N:6]1)[CH3:12]
Reactant: CCOC(OCC)c1nc(C)n(CC)n1
Agent: Cl
Solvent: O
Product: CCn1nc(C=O)nc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.4 %

Procedure:
A mixture of 3-(diethoxymethyl)-1-ethyl-5-methyl-1H-[1,2,4]triazole from step 1 (56.86 g, 0.267 mol) and H2O (300 mL) was treated slowly with 35% aqueous HCl (55.61 g, 0.534 mol), and the reaction was stirred at room temperature for 24 h. The mixture was washed with DCM (2×200 mL). The aqueous phase was basified to pH 13 with NaOH, and washed with DCM (3×200 mL). The combined DCM extracts were discarded. The aqueous phase was neutralized to pH 7 with HCl, and extracted with DCM (3×200 mL). The organic phase from this last extraction, containing the product, was dried over Na2SO4, and the solvent was removed under vacuum, affording 9.8 g (26%) of 1-ethyl-5-methyl-1H-[1,2,4]triazole-3-carbaldehyde which was 96% pure by NMR. 1H NMR (500 MHz, CDCl3): δ 1.49 (t, J=7.5 Hz, 3H), 2.51 (s, 3H), 4.20 (q, J=7.5 Hz, 2H), 9.91 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 12.1, 14.9, 44.4, 154.0, 159.2, 184.0. LC-MS (APCI) calcd for C6H9N3O: 139.07, found (M+H+): 140.1 m/z. Anal calcd for C6H9N3O: C, 51.79; H, 6.52; N, 30.20. Found: C, 51.5; H, 6.38; N, 29.98.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](I)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2].[Li]CCCC.Cl[C:21]([O:23][CH3:24])=[O:22]>O1CCCC1>[CH2:1]([C:3]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([C:21]([O:23][CH3:24])=[O:22])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCc1cc(CC)c(C(=O)O)cc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(CC)c(C(=O)OC)cc1C(=O)O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 24.8 %

Procedure:
To a stiffed solution of 2,4-diethyl-5-iodobenzoic acid (compound 204.4., 500 mg, 1.64 mmol, 1.00 equiv, 90%) in tetrahydrofuran (20 mL) at −78° C. under nitrogen was added dropwise a solution of n-BuLi (1.73 mL, 4.10 mmol, 2.36 M in THF). After 5 minutes, a solution of methyl chloroformate (0.315 mL, 4.10 mmol, 2.50 equiv) in THF (5 mL) was added dropwise to the reaction at −78° C. over 5 minutes. The reaction was stirred for another 5 min at −78° C., and then carefully quenched with 10 mL of water. The pH was adjusted to 1-2 with hydrochloric acid (6 M) and the resulting mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with 20 mL of brine, then dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatograph with ethyl acetate-petroleum ether (1:20) as eluent to yield 96 mg (25%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH:13]([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=NN(C)C.C(OCC)(=[O:24])C>O1CCCC1.P([O-])([O-])([O-])=O.O.O.[Cu](Cl)Cl>[CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH:13]([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:24]
Reactant: COC(CC1CC(C)c2ccccc2C1=NN(C)C)OC
Reactant: CCOC(C)=O
Agent: Cl[Cu]Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(CC1CC(C)c2ccccc2C1=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(Dimethylhydrazono)-1,2,3,4-tetrahydro-4-methyl-2-naphthaleneacetaldehyde dimethyl acetal (23.1 g) was dissolved under argon in a mixture of 1000 ml of tetrahydrofuran and 350 ml of 0.067M phosphate buffer of pH value 7. The solution was treated with 13.6 g of copper(II) chloride dihydrate and stirred at room temperature for 16 hours. 500 ml of ethyl acetate were added to the reaction mixture and it was washed three times with a mixture of 25% ammonia solution and saturated ammonium chloride solution (1:19) (1×800 ml, 2×500 ml). The aqueous wash phases were extracted twice with 500 ml of ethyl acetate each time, the organic phases were combined, dried over MgSO4 and freed from solvent. There were obtained 20.0 g of crude 1,2,3,4-tetrahydro-4-methyl-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal which was processed without purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.N1C=CC=CC=1C1C=C[C:22]([CH:23]=[O:24])=CC=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:22]/[CH:23]=[O:24])=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Product: O=C/C=C/c1ccnc2ccccc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 31 by substituting 4-quinolinecarboxaldehyde for the 4-(2-pyridinyl)-benzaldehyde of Reference Example 31. MS 184 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29].O.[NH2:33][NH2:34].O>CN(C=O)C>[N+:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1)([O-:30])=[O:29]
Reactant: O=C(CCc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(CCc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(2-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (837 mg, 2.0 mmol, prepared in Synthetic Example 10) in DMF (20 ml) was added hydrazine monohydrate (80%, 350 μl, 8.74 mmol, 4.4 eq.), and the mixture was then stirred at 100 to 110° C. overnight. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-[2-(2-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (790 mg, 95%).
Reaction SMILES: [C:1]([CH:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]([NH:13][CH:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]1=[O:28])[CH3:5])([OH:3])=[O:2].Cl.[CH2:30](O)[CH3:31]>>[CH2:30]([O:2][C:1]([CH:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]([NH:13][CH:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]1=[O:28])[CH3:5])=[O:3])[CH3:31]
Reactant: CCO
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@H]1CCCCN(C(C)C(=O)O)C1=O
Agent: Cl
Product: CCOC(=O)C(CCc1ccccc1)N[C@H]1CCCCN(C(C)C(=O)OCC)C1=O
Reaction time: 8 h

Procedure:
A solution of 1-(1-carboxyethyl)-3-(S)-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one (2.94 g.), a diastereoisomeric mixture prepared as in Example 13 from Isomer A of Example 12, with 40 ml. of ethanol was cooled to 0° and saturated with hydrogen chloride. After standing overnight at room temperature the solution was concentrated under vacuum. Dissolution in water, adjustment to pH 7, extraction with ether and concentration gave product as a colorless oil, weight 2.87 g. Tlc on silica gel indicated the presence of two diastereomers. If desired, the isomers may be separated by chromatography on silica gel and elution with hexane-ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[C:8]1(=O)[CH2:11][CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH:8]1([NH:7][C:4]2[NH:3][C:2]([CH3:1])=[N:6][N:5]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: Cc1nnc(N)[nH]1
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc(NC2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To a solution (30 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and cyclobutanone (2.1 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.4 g, 61%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:14])[O:13][CH:11]([CH3:12])[CH2:10]1.Cl>[OH-].[Na+]>[OH:13][CH:11]([CH3:12])[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: CC1CC(=O)O1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(O)CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
0.3 g of sodium hydroxide was added to 64.8 g of benzylalcohol and the reaction mixture was cooled to 0° C. To this reaction mixture was added 12.9 g of β-butyrolactone and the mixture was stirred for 5 minutes at 0° C. and for 2 hours at room temperature. After reaction, the reaction solution was neutralized by adding 15 ml of 1N-HCl solution and the separated organic layer was washed with saturated sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The resulting organic layer was distilled under reduced pressure to give 23.3 g (79%) of benzyi 3-hydroxybutanoate [Compound (11)] as oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[Br:16][C:17]1[C:23]([CH3:24])=[CH:22][C:20]([NH2:21])=[C:19]([CH3:25])[CH:18]=1.Cl>C(O)(C)C.CCOC(C)=O>[Br:16][C:17]1[C:23]([CH3:24])=[CH:22][C:20]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[C:5]([Cl:15])=[CH:4][N:3]=2)=[C:19]([CH3:25])[CH:18]=1
Reactant: Cc1cc(Br)c(C)cc1N
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(Br)cc3C)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
A mixture of 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (732 mg, 3 mmol), 4-bromo-2,5-dimethylaniline (554 mg, 2 mmol) and conc. aqueous HCl (1.5 mL) in iso-propanol (15 mL) was heated in a microwave for 40 min at 130° C. LCMS showed that the reaction was not complete, and additional 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (732 mg, 3 mmol) was added to the reaction. The reaction was again heated in a microwave for an additional 60 min at 130° C. The crude reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with saturated aqueous NaHCO3 (2×20 mL) and brine (10 mL), dried over Na2CO3 and concentrated in vacuo. The crude product was purified by silica chromatography (0-10% MeOH in EtOAc gradient with 1% NH3 additive) to give N2-(4-bromo-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as an off-white solid; ESMS m/z 407.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([F:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:27]1[C:32]2=[N:33][CH:34]=[CH:35][N:36]=[C:31]2[CH:30]=[C:29]([Cl:37])[N:28]=1>C1COCC1>[Cl:37][C:29]1[N:28]=[C:27]([NH:1][CH2:2][C:3]2([F:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:4]2)[C:32]2=[N:33][CH:34]=[CH:35][N:36]=[C:31]2[CH:30]=1
Reactant: Clc1cc2nccnc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCCC(F)(CN)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(F)(CNc2nc(Cl)cc3nccnc23)C1
Yield: 26.8 %

Procedure:
tert-butyl 3-(aminomethyl)-3-fluoropiperidine-1-carboxylate (3.86 g, 16.6 mmol) and DIPEA (3.22 g, 24.9 mmol) were added to a solution of 5,7-dichloropyrido[3,4-b]pyrazine (3.32 g, 16.6 mmol) in THF (60 mL) and the mixture was refluxed overnight. The volatile components were evaporated and the residue was extracted with ethyl acetate. Ethyl acetate was washed with brine and dried. The solvent was removed in vacuo The crude residue was purified by silica-gel chromatography eluting with Hexane-50% EtOAc/Hexane (gradient) then C18 column to afford the subtitled compound as pale yellow solid 1.76 g. MS (m/z): 396 (M+H)+
Reaction SMILES: [C:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:11]2[C:10]([CH3:16])([CH3:15])[CH2:9][CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH:5]=1)(=[O:3])C.Cl[O-].[Na+].S(=O)(O)[O-:23].[Na+]>O1CCOCC1>[CH3:14][C:13]1[C:4]([C:1]([OH:23])=[O:3])=[CH:5][C:6]2[C:7]([CH3:17])([CH3:18])[CH2:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]=2[CH:12]=1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: Cc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 8.2 g (0.0336 mol) of 2-acetyl-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene, 90 ml of 1.19M (0.107 mol) aqueous sodium hypochlorite and 10 ml of dioxane was stirred at room temperature for 0.5 hours and at 60° C. for 2 hours. A further 70 ml of 1.19M (0.0833 mol) of aqueous sodium hypochlorite was then added to the reaction mixture and the mixture stirred at 70° C. for 1 hours. The reaction mixture was then cooled and treated with aqueous sodium bisulfite solution until the mixture was negative to starch/iodide paper. The mixture was washed with ether and then acidified with H2SO4. The mixture was extracted with three portions of ether and the ether extracts were then combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The ether solution was then concentrated and the title compound obtained as colorless crystals by recrystallization from cold ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][C:20]1[CH:24]=[N:23][NH:22][C:21]=1[C:25](O)=[O:26]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:21]3[NH:22][N:23]=[CH:24][C:20]=3[CH3:19])=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: Cc1cn[nH]c1C(=O)O
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: Cc1cn[nH]c1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OCC2(F)F)c1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-methyl-2H-pyrazole-3-carboxylic acid (CAS82231-51-4; B. Pelcman et al., WO2006032851) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=368.1 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[C:6]3[C:13](OS(C(F)(F)F)(=O)=O)=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15]([CH3:17])=[N:16][C:5]2=3)[CH2:3][CH2:2]1.[Cl:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[C:35]([CH3:42])=[C:36]2[C:41]=1[O:40][CH2:39][CH2:38][CH2:37]2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:31][C:32]1[CH:33]=[C:34]([C:13]2[C:6]3[C:7]4[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=4[N:4]([CH:1]4[CH2:3][CH2:2]4)[C:5]=3[N:16]=[C:15]([CH3:17])[C:14]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:35]([CH3:42])=[C:36]2[C:41]=1[O:40][CH2:39][CH2:38][CH2:37]2
Reactant: CCOC(=O)c1c(C)nc2c(c3c(n2C2CC2)CCCC3)c1OS(=O)(=O)C(F)(F)F
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(Cl)c2c1CCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(c3c(n2C2CC2)CCCC3)c1-c1cc(Cl)c2c(c1C)CCCO2
Temperature: 90 °C
Yield: 95.2 %

Procedure:
A mixture of ethyl 9-cyclopropyl-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (500 mg, 1.120 mmol), 2-(8-chloro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.415 g, 1.344 mmol), and Na2CO3 (0.356 g, 3.36 mmol) in 1,4-dioxane (8.8 ml) and water (2.2 ml) was degassed with N2 for 5 min, treated with Pd(Ph3P)4 (0.129 g, 0.112 mmol), degassed with N2 for 5 min, and then heated to 90° C. for 2 hours. The reaction was cooled to rt, diluted with water, extracted with EtOAc 2×, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-40% EtOAc/Hexane) gave ethyl 4-(8-chloro-5-methylchroman-6-yl)-9-cyclopropyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (510.8 mg, 1.066 mmol, 95% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.00 (s, 1 H), 4.33-4.23 (m, 2 H), 4.03 (q, J=7.1 Hz, 2 H), 3.17-3.06 (m, 1 H), 2.80 (t, J=5.9 Hz, 2 H), 2.74-2.61 (m, 5 H), 2.17-2.06 (m, 2 H), 1.91-1.70 (m, 7 H), 1.65-1.57 (m, 2 H), 1.20-1.06 (m, 4 H), 0.98 (t, J=7.1 Hz, 3 H); LCMS (m/z) ES+=479 (M+1).