Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[O:12][CH3:13]>CO.[Ni]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][C:5]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(C#N)cc1OC
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1ccc(CN)cc1OC
Yield: 37.4 %

Procedure:
A solution of 4-cyano-2-methoxy benzoic acid (1.0 g, 5.65 mmol, Biogene) in methanol was reacted with p-toluenesulfonic acid monohydrate (285.6 mg, 1.479 mmol) and heated to reflux for 16 hrs. The solvent was removed and the reaction residue was extracted with EtOAc, and washed with saturated sodium carbonate, water, and saturated NaCl, and dried over Na2SO4 to give 4-Cyano-2-methoxy-benzoic acid methyl ester (1.04 g, 96%). This ester (1.01 g, 5.28 mmol) in methanol (50 mL) was reacted with Raney Ni (3 spatula tips full, exact amount unknown, Aldrich) under 50 psi H2 in a Parr apparatus for 16 hrs. After filtering through Celite and concentrating, the crude mixture was purified by silica gel chromatography using methanol and methylene chloride to give 4-aminomethyl-2-methoxy-benzoic acid methyl ester (385.7 mg, 37%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([CH3:8])=[N:6][N:7]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH3:1][N:2]([C:3]1[S:4][C:5]([CH3:8])=[N:6][N:7]=1)[C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNc1nnc(C)s1
Solvent: c1ccncc1
Product: Cc1nnc(N(C)C(=O)c2ccccc2)s1

Procedure:
2-(N-Methyl-amino)-5-methyl-1,3,4-thiadiazole (6 g, 0.046 mole) in pyridine (190 ml) was refluxed for 6 hours with benzoyl chloride (9.7 g, 0.069 mole) and the pyridine then evaporated off under reduced pressure. The residue was treated with water, made alkaline with sodium hydroxide solution and extracted with chloroform. The chloroform was washed with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride, dried, filtered and evaporated to yield title product which was recrystallised from ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38](F)(F)F)[CH:30]=2)[C:3]1=[O:42].CC1(C)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(=O)N(C2C=CC([N+]([O-])=O)=C(C)C=2)C1=O>>[CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:26])([F:27])[C:22]([F:25])([F:23])[F:24])=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([CH3:38])[CH:30]=2)[C:3]1=[O:42]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Agent: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1[N+](=O)[O-]
Product: Cc1cc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1[N+](=O)[O-]
Yield: 50 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 23 replacing the compound of Example 1. A colourless oil is obtained with a yield of 50%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]1[S:10][C:9]2[S:11][C:12](=[C:14]3[S:18][C:17]([C:19]([O:21]C)=[O:20])=[CH:16][S:15]3)[S:13][C:8]=2[S:7]1.O1CCOCC1.[Li+].[OH-].Cl>CO.C1COCC1>[S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]1[S:7][C:8]2[S:13][C:12](=[C:14]3[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][S:15]3)[S:11][C:9]=2[S:10]1
Reactant: COC(=O)C1=CSC(=C2SC3=C(SC(=C4SC=CS4)S3)S2)S1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=CSC(=C2SC3=C(SC(=C4SC=CS4)S3)S2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
10 (125 mg, 0.285 mmol) was suspended in a mixed solvent of 1,4-dioxane (50 ml), THF (50 ml), and MeOH (50 ml). The resultant mixture was charged with 2 N LiOH (28.5 ml, 57.0 mmol). The mixture was vigorously stirred for 15 hours at room temperature, then 2 N HCl (28.5 ml) was gradually added dropwise, and the mixture was adjusted to a pH of 2 to 3 by further adding 2 N HCl (2.0 ml) while checking the pH. The mixture was stirred for 20 minutes at room temperature, and then filtered using a membrane filter (H010A047A, Advantec). The filtered product was successively washed with water, methanol, and then chloroform, and dried under reduced pressure to obtain the target product Compound 1 (110 mg, 91%) as a glossy silvery-red film-like solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:18])([F:17])[C:12](B(O)O)=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]([C:11]([F:18])([F:17])[F:10])=[CH2:13])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: C=C(B(O)O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)nc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Yield: 91.1 %

Procedure:
2,6-dichloro-4-iodopyridine (0.87 g), (3,3,3-trifluoroprop-1-en-2-yl)boronic acid (purity: 65%, 0.75 g) and potassium carbonate (0.96 g) were dissolved in the mixed solvent of THF and water, which was then degassed three times. To the solution was added dichlorobis(triphenylphosphine) palladium (II) (0.04 g), and the mixture was heated to reflux for 3 hours under argon atmosphere. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with hexane. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under reduced pressure, and the residue was then purified by silica gel chromatography to obtain 2,6-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (0.70 g) at a yield of 82%.
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+].O>C(O)(C)C>[C:1]([S:14]([N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH3:21])(=[O:15])=[O:16])([C:4]([C:7]([C:10]([F:11])([F:13])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCCCN(CC(=O)OCC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCN(CC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 56 °C

Procedure:
A one-liter flask fitted with a thermocouple, addition funnel, heating mantle, reflux condenser and overhead stirrer was charged with C4F9SO2NH(C4H9) (133.0 g; 0.375 mole), and sodium carbonate (33.0 g). The mixture was heated to 93° C. and ethyl bromoacetate (69.0 g; 0.411 mole) was slowly added over a period of 8 hours, and then the ensuing mixture was allowed to stir overnight at 93° C. To this mixture was added water (120.0 mL) and the temperature was 56° C., at which point sulfuric acid (39.0 g; concentrated) at a rate to keep the temperature below 100° C. Two phases formed and the bottom layer was recovered and washed with water (150 mL). This crude material was distilled (110-125° C.; 3.3 mm Hg) to yield C4F9SO2N(C4H9)CH2CO2C2H5 (107.0 g). A one-liter flask fitted with a thermocouple, addition funnel, heating mantle, reflux condenser and overhead stirrer was charged with C4F9SO2N(C4H9)CH2CO2C2H5 (103.0 g; 0.241 mole) KOH (18.0 g; 0.273 mole) water (50 mL) and isopropanol (50.0 g). The mixture was heated at reflux for 2 hours, and a Dean-Stark trap was added. As isopropanol was removed from the trap, an equivalent amount of water was added to the reaction mixture. When the reaction mixture reached 101° C. water (25 mL) was added and the mixture was cooled to 56° C.; upon addition of sulfuric acid (26.7 g; concentrated) the temperature rose o 78° C. and two phases appeared. The bottom phase was distilled (139-147° C.; 3.6 mm Hg) to yield a creme colored solid, C4F9SO2N(C4H9)CH2CO2H.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:28][CH2:29][OH:30])[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:16]=2)[CH2:10][CH2:9]1.CC([O-])=O.[Na+].CC(O)=O.[Cl:40]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC#N.O.C(Cl)Cl>[Cl:40][C:18]1[CH:19]=[CH:20][C:15]([N:11]2[CH2:10][CH2:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])([CH2:28][CH2:29][OH:30])[O:13][C:12]2=[O:14])=[N:16][C:17]=1[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1
Reactant: O=C1OC(CCO)(c2ccccc2F)CCN1c1cccc(-c2ccc(F)cc2)n1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: O=C1OC(CCO)(c2ccccc2F)CCN1c1ccc(Cl)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.2 %

Procedure:
A mixture of 6-(2-fluorophenyl)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (30 mg, 0.07 mmol), NaOAc (9 mg, 0.11 mmol) in HOAc (4 mg, 0.07 mmol), CH3CN (2 mL), H2O (0.1 mL) and CH2Cl2 (2 mL) was stirred at rt for 5 min. A solution of 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (37 mg, 0.11 mmol) in CH3CN (0.5 mL) was added slowly. The mixture was stirred for 20 min and heated to 40° C. for 2 h. The reaction was quenched with aq NaHSO3 and extracted with CH2Cl2. The organic layer was dried with Na2SO4, concentrated to afford the crude product. Purification afforded 3-(5-chloro-6-(4-fluorophenyl)pyridin-2-yl)-6-(2-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (15 mg, 48%). LC-MS Method 3, tR=1.331 min, m/z=445. 1H NMR (CDCl3, 400 Hz): 2.40 (m, 3H), 2.84 (m, 1H), 3.40 (m, 1H), 3.66 (m, 1H), 3.82 (m, 1H), 4.26 (m, 1H), 7.10 (m, 3H), 7.18 (m, 1H), 7.34 (m, 1H), 7.50 (m, 1H), 7.68 (m, 2H), 7.76 (m, 1H), 8.01 (m, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:37]=[C:36]([NH:38][C:39]([N:41]2[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:42]2=[O:52])=[O:40])[CH:35]=[CH:34][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]3[N:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)[S:14][C:7]=12>C(Cl)Cl>[F:2][C:3]1[CH:37]=[C:36]([NH:38][C:39]([N:41]2[CH2:45][CH2:44][N:43]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:42]2=[O:52])=[O:40])[CH:35]=[CH:34][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][NH:22][CH2:30][CH2:31][O:32][CH3:33])=[CH:19][N:20]=3)[S:14][C:7]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccccc6)C5=O)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccccc6)C5=O)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
HCl gas was bubbled into a solution of 127 (61 mg, 0.08 mmol) in DCM. The flask was capped and the mixture was stirred at room temperature for 30 min. Formed precipitate was collected by filtration and washed with DCM to afford 128 (52 mg, 84% yield), presumably as a trihydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.59 (s, 1H), 9.34 (br.s, 2H), 8.75 (s, 1H), 8.62 (d, J=5.7 Hz, 1H), 8.43 (s, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.15 (dd, J=8.2, 2.1 Hz, 1H), 7.86 (dd, J=12.9, 2.4 Hz, 1H), 7.62 (d, J=7.6 Hz, 2H), 7.4-7.6 (m, 4H), 7.17 (t, J=7.3 Hz, 1H), 6.81 (d, J=5.5 Hz, 1H), 4.25 (m, 2H), 3.95 (m, 4H), 3.62 (m, 2H), 3.29 (s, 3H), 3.13 (br.s, 2H). MS (m/z): 613.3 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:24][N:23]=3)=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:44][NH2:45]>C1COCC1>[CH3:44][NH:45][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:24][N:23]=3)=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(-c2cnccc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)ccn1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNc1cc(-c2cnccc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)ccn1
Temperature: 0 °C

Procedure:
A high pressure steel bomb was charged with N-(4-(3-(2-fluoropyridin-4-yl)pyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine (0.115 g, 0.237 mmol), potassium carbonate (0.049 g, 0.355 mol) and 3.0 mL of THF. The bomb was sealed, cooled to 0° C. and pressurized with methylamine gas. The reaction mixture was allowed to warm to RT, and heated at 80° C. for 45 h. Upon cooling, the reaction mixture was filtered through a fritted funnel, washed with MeOH, and concentrated. This mixture was purified by silica gel chromatography, (ISCO, 40 g column 0-10% MeOH/dichloromethane) to provide N-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine as a light yellow solid. MS m/z=497 [M+H]+. Calc'd for C31H24N6O: 496.56.
Reaction SMILES: C([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([CH:16]([CH3:18])[CH3:17])=[N:11]2)CCC.Cl>O1CCCC1>[F:23][C:21]1[CH:20]=[CH:19][C:9]2[C:10]([CH:16]([CH3:17])[CH3:18])=[N:11][C:12]3[CH:13]=[CH:14][NH:15][C:6](=[O:5])[C:7]=3[C:8]=2[CH:22]=1
Reactant: CCCCOc1nccc2nc(C(C)C)c3ccc(F)cc3c12
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)c1nc2cc[nH]c(=O)c2c2cc(F)ccc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-butoxy-9-fluoro-6-isopropylbenzo[c]-1,6-naphthyridine (33 mg, 0.11 mmol) in tetrahydrofuran (1.0 ml) was added 6N HCl (1.0 ml). The reaction mixture was stirred at 100° C. for 2 h, and then cooled to room temperature. The yellow precipitate was collected by vacuum filtration (rinsing the filter cake with THF) to afford 9-fluoro-6-isopropylbenzo[c]-1,6-naphthyridin-1(2H)-one (HCl salt). 1H NMR (500 MHz, DMSO-D6) δ 11.89 (br s, 1H), 9.76 (dd, 1H), 8.59 (dd, 1H), 7.63 (dt, 1H), 7.59 (t, 11-1), 6.79 (d, 1H), 6.33 (br peak, HCL/H2O), 4.09 (septet, 1H), 1.37 (d, 6H). LRMS (ESI) calc'd for (C15H13FN2O) [M+H]+, 257.1; found 257.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[C:5]([C:7]1[C:12]([O:13]COC)=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].S(=O)(=O)(O)O.CC(C)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[C:5]([C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: COCOc1cccnc1C(=O)c1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1ccc(F)c(Br)c1)c1ncccc1O
Yield: 91.2 %

Procedure:
A mixture of 2-(3-bromo-4-fluorobenzoyl)-3-methoxymethoxypyridine (5.68 g), 3.6N-sulfuric acid (6.0 mL) and acetone (30 mL) was refluxed for 3 hours. The reaction mixture was then poured into water, neutralized with a saturated aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromo-4-fluorobenzoyl)-3-hydroxypyridine (4.51 g) (compound C-5). Physical properties and spectrum date of the product are shown in Table 5 and Table 6.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:15][CH3:16])C.O.[NH2:19][NH2:20]>C(O)C>[CH2:15]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:7]=1[NH:6][CH2:5][C:4]([NH:19][NH2:20])=[O:3])[CH3:16]
Reactant: CCOC(=O)CNc1c(CC)cccc1CC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1cccc(CC)c1NCC(=O)NN

Procedure:
58.7 g (0.25 mol) of 2,6-diethyl-anilino-acetic acid ethyl ester and 25 g of hydrazine hydrate were left to stand in 200 ml of ethanol for 24 hours. Thereafter, the mixture was concentrated by distilling off the solvent and the residue was extracted by stirring with water. After drying, 50.5 g (91% of theory) of colorless crystals of 2,6-diethyl-anilino-acetic acid hydrazide of melting point 71° to 73° C. were obtained.
Reaction SMILES: [CH:1]1([N:4]([C:12]2[N:17]3[N:18]=[CH:19][CH:20]=[C:16]3[N:15]=[C:14](SC)[N:13]=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>S1C=CC=C1C([O-])=O.[Cu+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([N:4]([C:12]2[N:17]3[N:18]=[CH:19][CH:20]=[C:16]3[N:15]=[C:14]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:35])[F:36])[CH:27]=3)[N:13]=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CSc1nc(N(C(=O)OC(C)(C)C)C2CC2)n2nccc2n1
Agent: [Cu+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N(c1nc(-c2cccc(OC(F)(F)F)c2)nc2ccnn12)C1CC1
Temperature: 50 °C
Yield: 85.9 %

Procedure:
Note: THF was degassed with a stream of N2 for 10 min. in a separate flask. Tert-butyl cyclopropyl(2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)carbamate (100 mg, 0.31 mmol), 3-(trifluoromethoxy)phenyl boronic acid (154 mg, 0.74 mmol), tri(2-furyl)phosphine (86 mg, 0.37 mmol), copper(I) thiophene-2-carboxylate (167 mg, 0.88 mmol), Pd2dba3 (24 mg, 0.03 mmol) were combined. The flask was evacuated and backfilled with N2. THF (3.7 mL) was added and the reaction was heated to 50° C. for 5 d. The solution was diluted with Et2O (40 mL) and washed with 10% NH4OH (3×30 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The solid residue was triturated with Et2O and filtered. The filtrate was concentrated in vacuo and purified via flash column chromatography (2.5-5% EtOAc/hexanes) to afford tert-butyl cyclopropyl(2-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)carbamate (116 mg, 85%). LCMS (ES): >95% pure, m/z 436 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: COCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CCOC)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 33.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.9 mg) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]=[C:11]([S:14][CH3:15])SC)=[CH:5][CH:4]=1.O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1>C(O)(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][C:11]([S:14][CH3:15])=[N:26]2)=[CH:21][CH:20]=1
Reactant: NNc1ccc(F)cc1
Reactant: CSC(=CC(=O)c1ccc(SC)cc1)SC
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(-c2cc(SC)nn2-c2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 7 h
Yield: 22.1 %

Procedure:
A mixture of 1-[4-(methylthio)phenyl]-3,3-bis-(methylthio)-2-propen-1-one (2.7 g) and 4-fluorophenylhydrazine hydrate (1.8 g) in acetic acid (15 ml) was stirred at 100 ° C. for 7 hours. The solvent was evaporated and the residue was dissolved in ethanol. The insoluble material was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (25 g) eluting with chloroform to give an oil of 1-(4-fluorophenyl)-3-(methylthio)-5-[4-(methylthio)phenyl]pyrazole (0.73 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13]C)=O>C1COCC1.Cl>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:9]=[CH:10][C:11](=[O:13])[NH:1]2)=[CH:4][CH:5]=1
Reactant: COC(=O)/C=C/c1ccc(F)cc1N
Agent: Cl
Solvent: C1CCOC1
Product: O=c1ccc2ccc(F)cc2[nH]1
Temperature: 65 °C
Yield: 81.1 %

Procedure:
A mixture of (E)-methyl 3-(2-amino-4-fluorophenyl)acrylate (30.38 g, 156 mmol) in THF (400 mL) and 3M hydrochloric acid (400 mL) was heated at 65° C. for 20 h. The mixture was cooled to RT and poured onto ice. The resulting precipitate was filtered, washed with copious amounts of water and dried in vacuo to give 20.65 g (81%) of a light-yellow amorphous solid. m/z=164 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)[CH3:3].[C:18]([OH:27])(=[O:26])[C@H:19]([C@@H:21]([C:23]([OH:25])=[O:24])[OH:22])[OH:20]>CC(C)=O>[C:23]([C@H:21]([C@@H:19]([C:18]([OH:27])=[O:26])[OH:20])[OH:22])([OH:25])=[O:24].[CH2:2]([O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)[CH3:3]
Reactant: CCOc1ccccc1OC1CCCNC1
Agent: Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CC(C)=O
Product: CCOc1ccccc1O[C@@H]1CCCNC1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A slurry of 3-(2-ethoxyphenoxy)piperidine hydrochloride (200 g, 0.776 mol) and D-tartaric acid (118 g, 776 mol) in acetone (3.0 L) was warmed to 56° C. and was held at that temperature for 2 hours. The mixture was cooled to 20° C. and was held at that temperature overnight. The crystals were collected by filtration, rinsing with acetone (1 L), and then were dried to afford (R)-3-(2-ethoxyphenoxy)piperidine D-tartrate (145 g). Chiral HPLC analysis indicated an enantiomeric ratio of 99.5:0.5 (Chiralpak AD-H, 4.6×250 mm, 5 μm, 210 nM, 0.2% isopropylamine-isopropanol, 0.7 mL/min; retention times 5.76 min (major enantiomer), 6.20 min (minor enantiomer). 1H NMR (400 MHz, DMSO-d6) δ 12.69 (br s, 1.5H), 9.34 (br s, 1H), 8.79 (br s, 1H), 7.12 (d, 1H), 7.03 (m, 2H), 6.89 (m, 1H), 5.09 (br s, 1.5H), 4.44 (m, 1H), 4.32 (s, 2H), 4.05 (q, 2H), 3.28 (m, 1H), 3.11 (m, 1H), 3.04 (m, 2H), 1.97 (m, 1H), 1.92 (m, 1H), 1.72 (m, 2H), 1.35 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([NH2:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(O)(C)C>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([NH:29][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: CC(C)(C)CN
Solvent: CC(C)O
Product: CCCC(C(=O)OC)c1c(C)nc(NCC(C)(C)C)nc1-c1ccc(C)cc1
Yield: 49.5 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), and neopentyl amine (0.177 mL; 1.502 mmol) were placed in a 2 mL reaction tube and dissolved in isopropanol (1.5 mL). The tube was sealed and irradiated in a microwave oven at 180° C. for 1 h. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 57 mg (49%) of the title compound as a colorless oil.