Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C([N-][CH:12]([CH3:14])[CH3:13])(C)C.[Li+].C1(Br)CC1.[Cl-].[NH4+]>O1CCCC1>[CH:12]1([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:14][CH2:13]1
Reactant: Cc1ccncc1
Reactant: CC(C)[N-]C(C)C
Agent: BrC1CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1cc(CC2CC2)ccn1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
A solution of 19.5 ml (200 mmol) of 4-picoline in tetrahydrofuran (120 ml) was cooled to −78° C. Lithium diisopropylamide (2 M heptane, tetrahydrofuran, ethylbenzene solution) (200 ml) was added dropwise to the cooled solution over a period of 20 min, and the mixture was stirred at −40° C. for 20 min and was then cooled to −78° C. Cyclopropyl bromide (16.0 ml, 200 mmol) was added dropwise to the reaction solution over a period of 25 min, and the mixture was stirred at −78° C. for one hr. The reaction solution was then added to 300 ml of a saturated aqueous ammonium chloride solution, and the mixture was washed with 100 ml of water. The solution was extracted twice with 200 ml of ethyl acetate, and the extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by distillation under the reduced pressure (8 mmHg, 86 to 87° C.) and column chromatography on silica gel (hexane:ethyl acetate=70:30) to give 17.6 g (yield 66%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54].C([O-])([O-])=O.[Cs+].[Cs+]>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]>[NH2:29][CH:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[C:40]([F:53])[C:39]([OH:54])=[C:38]([Cl:37])[CH:43]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(Nc3c(S(C)(=O)=O)cnc4ccc(Br)cc34)cn2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(N)C2)nc1
Temperature: 140 °C
Yield: 22.9 %

Procedure:
To a suspension of tert-butyl 1-(5-(6-bromo-3-(methylsulfonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (70 mg, 0.121 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (40 mg, 0.145 mmol) and Pd(dppf)Cl2 (9 mg, 0.012 mmol) in dioxane (4 mL) was added Cs2CO3 (182 μL, 2.0 M solution in H2O). The reaction mixture was degassed using N2 and heated at 140° C. for 30 min. The reaction mixture was cooled to rt and to purification by preperatory HPLC. The crude mixture was then treated with TFA to deprotect the pendant amine and reduced to a red-orange residue. This residue was then dissolved in MeOH (2 mL) and treated with a 2.0 M HCl solution in diethyl ether to afford the product (15 mg, 19%) as a brown-yellow solid: 1H NMR (300 MHz, MeOD) δ 9.07 (s, 1H), 8.32 (d, J=2.7 Hz, 1H), 8.27 (dd, J=8.8, 1.9 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.88 (dd, J=9.3, 2.7 Hz, 1H), 7.28 (m, 1H), 7.09 (m, 2H), 4.56 (q, J=10.4, 9.4 Hz, 1H), 4.09 (d, J=13.3 Hz, 1H), 3.47 (s, 3H), 3.39 (d, 8.1 Hz, 2H), 2.21 (s, 1H), 2.01 (m, 1H), 1.75 (m, 2H); ESI MS m/z 542, [C26H25ClFN5O3S+H]+; HPLC 99.6% (AUC), tR=9.90 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: OB(O)c1ccc(O)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 100 °C
Yield: 2.5 %

Procedure:
To a mixture of 2-bromonaphthalene (4.0 g, 19.32 mmol), 4-hydroxyphenylboronic acid (2.9 g, 21.24 mmol), potassium phosphate (14.35 g, 67.61 mmol), tricyclohexyl phosphine (542 mg, 1.93 mmol), toluene (80 mL) and water (4 mL) was added palladium acetate (217 mg, 0.965 mmol) under N2. The reaction mixture was heated to 100° C. for 24 h and then cooled to rt. Water was added and the mixture was extracted with EtOAc. The organic layer was separated, washed with water, brine, dried and concentrated to give crude product. Purification by column chromatography using 10% EtOAc in hexane afforded 105 mg of 4-naphthalen-2-yl-phenol. MS (ES) m/z: 220.07 (M) and 219.04 (M−1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([F:48])([F:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:22]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O.C(N(CC)CC)C.[Br-].[Li+]>C(#N)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([F:47])([F:48])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:22]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)O
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)O)[C@@](O)(CCOC)C(=O)O
Temperature: 50 °C
Reaction time: 11.5 h
Yield: 54 %

Procedure:
(E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoic acid (No. 5514403, 100 mg, 0.142 mmol) was dissolved in acetonitrile (1.0 mL), and subsequently water (0.005 mL, 0.278 mmol), triethylamine (0.118 mL, 0.847 mmol) and anhydrous lithium bromide (244 mg, 2.81 mmol) were sequentially added at room temperature. The mixture was stirred at 50° C. for 11.5 hours. After cooling the reaction solution to room temperature, a preparative HPLC was performed to obtain 51.1 mg of the title compound (0.07629 mmol, 54% yield).
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:43]([O:47][C:48](=[O:54])[CH2:49][NH:50][C:51]([NH2:53])=[O:52])([CH3:46])([CH3:45])[CH3:44].C([O-])([O-])=O.[Cs+].[Cs+].C[O:62][C:63](=O)[C:64]1[CH:69]=[CH:68][N:67]=[CH:66][C:65]=1Br>CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O1CCOCC1>[C:43]([O:47][C:48](=[O:54])[CH2:49][N:50]1[C:63](=[O:62])[C:64]2[CH:65]=[CH:66][N:67]=[CH:68][C:69]=2[NH:53][C:51]1=[O:52])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)CNC(N)=O
Reactant: COC(=O)c1ccncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2cnccc2c1=O

Procedure:
A 2-5 ml microwave vial is charged with Pd(OAc)2 (2.5 mol %, 6.6 mg, 0.0231 mmol), Xantphos (5 mol %, 27.1 mg, 0.0463 mmol), ureido-acetic acid tert-butyl ester (259 mg, 1.482 mmol), and Cs2CO3 (770.2 mg, 2.315 mmol). 3-Bromo-isonicotinic acid methyl ester (216.3 mg, 0.926 mmol) is added, followed by 1,4-dioxane (4 ml). The vessel is sealed and treated in the microwave at 120° C. for 3×3600 seconds. EtOAc is added to the reaction mixture which is then washed with brine (3×20 ml) and water (2×10 ml). The organic phase is passed through Celite® (filter material), dried (MgSO4), filtered and concentrated. The material is purified via flash column chromatography, eluting with iso-hexane:EtOAc to afford the title compound; [M+H]+ 278.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[N:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:16](=[O:27])[CH2:17]2)=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: O=C1CN(c2ccncc2)CCN1c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CN(c2ccncc2)CCN1c1ccc(O)cc1

Procedure:
To a solution of the product of step (i) (1.1 g) in a mixture of methanol (500 ml) and tetrahydrofuran (100 ml) was added 30% palladium-on-charcoal catalyst (300 mg) and the mixture stirred in an atmosphere of hydrogen at ambient temperature and pressure until all the starting material had been consumed. After removal of the catalyst by filtration, the solvent was evaporated in vacuo to give 4-[4-(4-pyridyl)piperazin-2-one-1-yl]phenol as a colourless solid, essentially one spot by tlc, which was used without further purification or characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[N+](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-].CO>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:7][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[Cl:1])[CH3:19]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OCCOc1ccccc1Cl
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)COCCOc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.6 %

Procedure:
To a solution of 2-(2-chlorophenoxy)ethanol (1.73 mL, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (11 mg) followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reaction mixture is stirred at rt for 20 min. To the reaction mixture is added MeOH followed by rotary evaporated, and the residue is purified by chromatography on silica gel; elution with EtOAc:heptane (25:75) gives 1.36 g of the product 436. 1H NMR (CDCl3) δ 7.35 (d, 1H), 7.19 (d, 1H), 6.95-6.90 (m, 2H), 4.30 (s, 2H), 4.25-4.15 (m, 4H), 4.0 (t, 2H), 1.2 (t, 3H); MS: m/z 259 (M++1).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[C:37]([O:36][C:34]([N:28]1[CH2:33][CH2:32][N:31]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=[C:7]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[CH:8]=2)[CH2:30][CH2:29]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(COS(C)(=O)=O)c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Yield: 83.5 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethyl phenyl)-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 83.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C@@H:5]([CH2:26][CH:27]=C)[C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:10][C:9]1=[O:25])=[O:7].[O:34]=O.N#N.S(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C@H:5]([C:6](=[O:7])[N:8]1[C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:10][C:9]1=[O:25])[CH2:26][CH:27]=[O:34]
Reactant: C=CC[C@H](Cc1c(F)cccc1Cl)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reactant: O=O
Agent: N#N
Solvent: ClCCl
Solvent: CSC
Product: O=CC[C@H](Cc1c(F)cccc1Cl)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Dissolve (4S,5R)-3-((R)-2-(2-chloro-6-fluorobenzyl)pent-4-enoyl)-4,5-diphenyloxazolidin-2-one (1.05 g, 2.27 mmol) in CH2Cl2 (200 mL). Cool the solution to −78° C. Bubble O2 into the solution until the solution turns blue. Then bubble N2 for 5 minutes and add Me2S (0.706 g, 11.3 mmol). Stir the mixture for one hour and then remove the solvent. Purify the residue by chromatography (Silica gel) to afford (S)-3-(2-Chloro-6-fluorobenzyl)-4-oxo-4-((4S ,5R)-2-oxo-4,5-diphenyloxazolidin-3-yl)butanal (0.384 g, 36%). 1H NMR (CDCl3) δ 7.18 (m, 2H), 7.12 (m, 6H), 6.98 (m, 3H), 6.82 (m, 2H), 6.00 (d, 1H), 5.69 (d, 1H), 4.72 (m, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.92 (m, 1H), 2.61 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH2:16][OH:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([CH:16]=[O:17])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1onc(-c2ccccc2)c1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=Cc1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (Intermediate I-12A, 0.4 g, 1.645 mmol) in dichloromethane (5 mL) was added Dess-Martin Periodinane (0.767 g, 1.809 mmol) over a period of 2 min. at 0° C. under a nitrogen atmosphere. The milky suspension was stirred at 0° C. for 10 min. and at room temperature for 30 min. An additional 65 mgs of Dess-Martin reagent was added at room temperature and the contents were stirred at room temperature for 3 h. To the reaction mixture was added 10 mL of a 1:1 mixture of sat. aq. NaHCO3 and aq. sodium thiosulfate, slowly at room temperature. After stirring the reaction mixture for 10 min. at room temperature, the dichloromethane layer was separated and the aqueous layer re-extracted with dichloromethane (10 mL). The combined dichloromethane layers were dried over sodium sulfate and concentrated under reduced pressure to yield 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbaldehyde (0.385 g, 1.596 mmol, 97% yield) as an oil, which was used as such for the subsequent step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 10.14 (s, 1H) 7.63-7.70 (m, 2H) 7.47-7.60 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][N:4]([NH:9]C(=O)C)[C:5](=[O:8])[NH:6][N:7]=1.Cl.Cl.[NH2:15][N:16]1[CH2:21][C:20](C)=[N:19]NC1=O.[CH3:24][OH:25]>>[NH2:9][N:4]1[CH2:3][C:2]([CH3:1])=[N:7][NH:6][C:5]1=[O:8].[NH2:15][C:16]1[C:24](=[O:25])[NH:4][N:19]=[N:20][CH:21]=1
Reactant: CO
Reactant: CC(=O)NN1CC(C)=NNC1=O
Agent: CC1=NNC(=O)N(N)C1
Agent: Cl
Product: Nc1cnn[nH]c1=O
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A suspension is prepared of 39.9 g (0.234 mol) 6-methyl-4-acetylamino-4,5-dihydro-1,2,4-triazin-3-(2H)-one in 99 g 95% methanol. The suspension is heated to 45° C. and becomes a clear colourless solution. At between 45° and 50° C. a total of 15.4 g (0.421 mol) HCl are bubbled through this solution over a 2 to 3 hour period. After about 30% of the HCl has been added the reaction mixture is seeded with 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine hydrochloride. Thereafter 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4,-triazine precipitates out continuously as the hydrochloride salt. After about 2 hours stirring, the maximum conversion of over 99% is reached. The reaction mixture is brought to pH 5 by the addition of 50% NaOH solution. The free aminotriazinone 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine is formed in an amount of 29.7 g representing 14.3% by weight of the solution. This represents a yield of 99.2% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:12][N:13]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(C2=NNC(c3ccccn3)=NN2)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2nnc(-c3ccccn3)nn2)nc1
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of 3-(5-aminopyridin-2-yl)-6-(pyridin-2-yl)-1,4-dihydro-1,2,4,5-tetrazine (0.950 g, 3.8 mmol) in anhydrous toluene (25 mL) under N2 was added 2,3-dichloro-5,6-dicyanobenzoquinone (1.7 g, 7.5 mmol). The reaction mixture was allowed to reflux and stir for 12 hr. The reaction mixture was concentrated under reduced pressure, and the crude residue was concentrated in vacuo onto deactivated silica gel and chromatographed using a gradient (0-100%) of acetone in hexanes to give 771 mg (3.1 mmol, 81%) of the title compound as a red solid, mp 207-209° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH2:8][OH:9])[CH:7]=1>[Pd].CO.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: COc1ccc(/C=C/c2ccc(F)cc2CO)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: COc1ccc(CCc2ccc(F)cc2CO)cc1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of 6.8 g (26.33 mmol) of E-{5-fluoro-2-[2-(4-methoxyphenyl)vinyl]phenyl}methanol from Example 30A and 0.5 g of palladium on carbon (10%) in 50 ml of methanol and 250 ml of ethanol is hydrogenated under atmospheric pressure at room temperature for 1 hour. After reaction has stopped, the mixture is filtered through kieselguhr and the filtrate is then concentrated to dryness. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1→1:1). 5.95 g (87% yield) of a colorless solid are obtained.
Reaction SMILES: [NH2:1][C:2](=[S:16])[NH:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].[OH-].[Na+].CO.Cl>O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:4]2[C:5]([CH3:6])=[N:1][C:2]([SH:16])=[N:3]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N(NC(N)=S)C(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-n2nc(S)nc2C)cc1
Yield: 91 %

Procedure:
A mixture of 14.5 parts of acetic acid 2-(aminothioxomethyl)-1-(4-methoxyphenyl)hydrazide, 5 parts of sodium hydroxide and 80 parts of methanol is stirred and refluxed for 30 minutes. The reaction mixture is cooled and water is added. The whole is adjusted to pH 5 with a hydrochloric acid solution. The precipitated product is filtered off and dried, yielding 12.3 parts (91%) of 1-(4-methoxyphenyl)-5-methyl-1H-1,2,4-triazole-3-thiol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:26]([N:28]1[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29]1)=[O:27])[C@H:9]([CH:11]1[CH2:16][CH2:15][C:14]([C:17]2[N:22]3[N:23]=[CH:24][N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)=[CH:13][CH2:12]1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO.C(O)(=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:26]([N:28]1[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29]1)=[O:27])[C@H:9]([CH:11]1[CH2:12][CH2:13][CH:14]([C:17]2[N:22]3[N:23]=[CH:24][N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C1CC=C(c2cccc3ncnn23)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](C1CCC(c2cccc3ncnn23)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Reaction time: 1 h

Procedure:
The material from Step B (0.13 g, 0.27 mmol) was hydrogenated at 50 psi hydrogen in the presence of 10% palladium on carbon (0.13 g) in methanol (5 mL) containing 30 drops of acetic acid using a Parr shaker. After 1 h, the reaction mixture was filtered by passage through a syringe filter. The filtrate was concentrated and the residue was dissolved in chloroform and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (anhydrous sodium sulfate) and concentrated in vacuo. The residue was purified by silica gel chromatography (0-5% methanol in dichloromethane) gradient to afford the title compound. LC/MS 492.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[N+:18]([O-])=O.Br[C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29]>>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:29])[C:22]=1[C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([NH2:1])=[C:3]([NH2:18])[CH:4]=1
Reactant: Fc1cccc(F)c1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1N
Product: Cc1cc(-c2c(F)cccc2F)cc(N)c1N

Procedure:
The title compound was prepared from 2-methyl-6-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (as prepared in Example 8, step A) and 2-bromo-1,3-difluoro-benzene according to the procedures described in Example 4, step A and Example 1, step E. 1H-NMR (400 MHz, CDCl3) δ: 7.17 (tt, J=8.3, 6.3 Hz, 1H), 6.87-6.97 (m, 2H), 6.76 (s, 1H), 6.72 (s, 1H), 3.44 (br. s., 4H), 2.21 (s, 3H).
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][C:6]1[CH:7]=[C:8]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][NH:17][C@H:16]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1>CO>[ClH:4].[CH3:12][C:10]1[CH:9]=[C:8]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][NH:17][C@H:16]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:6]([CH3:5])[CH:11]=1
Reactant: CC(=O)Cl
Agent: Cc1cc(C)cc(CO[C@H]2CCCN[C@H]2c2ccccc2)c1
Solvent: CO
Product: Cl

Procedure:
Acetyl chloride (0.26 ml, 3.66 mmol) was added dropwise with stirring to anhydrous methanol (3.7 ml) and the resultant solution was added to a solution of cis-3-((3,5-dimethylphenyl)methyloxy)-2-phenylpiperidine (360 mg, 1.22 mmol) in anhydrous methanol (1 ml). The solvent was removed in vacuo, and the residue recrystallised from ethyl acetate-methanol to provide cis-3-((3,5-dimethylphenyl)methyloxy)-2-phenyl piperidine hydrochloride salt as a crystalline, white solid, m.p.=200°-225° C. (decomp). 1H NMR (360 MHz, DMSO-d6) δ7.44 (m), 6.82 (2), 6.56 (2), 4.49 (2), 4.41 (d, J=12.3 Hz), 4.09 (d, J=12.3 Hz), 3.80 (s), 3.05 (t, J=14.7 Hz), 2.14 (s), 1.90 (m), 1.72 (m); m/z (CI+) 296 (MH); Analysis: Found: C, 72.36; H, 7.91; N, 4.31. Calcd. for C20H26NOCl; C, 72.38; H, 7.90; N, 4.22%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].BrC1C=CC=CC=1.[C:12]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][C:13]1=[CH2:14].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:16](=[O:17])[CH2:15][C:13](=[CH2:14])[C:12]([OH:18])=[O:19])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: C=C1CC(=O)OC1=O
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Brc1ccccc1
Product: C=C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
21.2 g of anhydrous aluminum chloride are introduced into 50 g of bromobenzene and the mixture is cooled to 0° C. A solid mixture of 8.3 g of itaconic anhydride and 13.2 g of 4-chlorobiphenyl is added in portions in the course of one hour. The reaction mixture is stirred at 0° C. for two hours and then added to 100 g of ice water. The solid reaction product is filtered off and washed twice with water (50 ml). After recrystallization from ethyl acetate, the product is dried at room temperature and about 100 mbar until free of solvent and water. 4-(4′-Chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid is obtained in a yield of 50% as a colorless, finely crystalline powder.