Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12][CH2:13]2)(=[O:18])=[O:19])=[CH:21][CH:22]=1)(=[O:30])[CH:28]=[CH2:29]
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(NC(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
Diisopropylethylamine (0.14 ml, 0.8 mmol) was added in one portion to a stirred solution of N-[4-(4-amino-piperidine-1-sulfonyl)-phenyl]-acrylamide (0.1 g, 0.32 mmol) in THF (3 ml) at room temperature. To this mixture was added benzoyl chloride (0.048 ml, 0.42 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue purified by flash column chromatography (elution: 70% heptane, 30% ethyl acetate to 40% heptane, 60% ethyl acetate) to give the title compound (7 mg, 5% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1.[OH2:13]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([CH:8]=[O:13])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: O
Product: COc1ccc(C(=O)C=O)cc1

Procedure:
Dimethylslufoxide (50 ml) solution of 4-methyoxyphenacylbromide (9.94 g, 43.4 mmol) and water (1.6 ml, 88.8 mmol) were stirred at 50° C. for 2.5 hr. Water was added and the solution was extracted with ethyl acetate 3 times and washed with brine and then dried over sodium sulfate. Removal of the solvent gave 4-methoxyphenylglyoxal (8.30 g, quant.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=O)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([NH:19][NH2:20])=[O:18].C(O)(=O)C>CCO>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[N:20][NH:19][C:17](=[O:18])[C:16]2[CH:21]=[CH:22][CH:23]=[C:14]([CH3:13])[CH:15]=2)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1O
Reactant: Cc1cccc(C(=O)NN)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NNC(=O)c1cccc(C)c1)c1cc(Cl)cc(Cl)c1O
Temperature: 60 °C
Yield: 92.8 %

Procedure:
A suspension of 1-(3,5-dichloro-2-hydroxyphenyl)-ethanone (0.100 g, 0.49 mmol), 3-methylbenzoic acid hydrazide (0.069 g, 0.46 mmol), and glacial acetic acid (0.3 mL) in EtOH (3 mL) was heated to 60° C. for 4 h The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with H2O to furnish the title material as a yellow solid (0.144 g, 93%): mp 221-223° C.; 1H NMR (400 MHz, DMSO) δ 14.48 (s, 1H), 11.54 (s, 1H), 7.79-7.72 (m, 2H), 7.68 (d, J=2.5 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.47-7.42 (m, 2H), 2.52 (s, 3H), 2.41 (s, 3H); ESIMS m/z 337 ([M+H]+), 335 ([M−H]−).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:47][C:44]4[CH:45]=[CH:46][C:41]([N:38]5[CH2:39][CH2:40][CH:35]([CH2:34][N:31]6[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]6)[CH2:36][CH2:37]5)=[CH:42][CH:43]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: CN1CCN(CC2CCN(c3ccc(N)cc3)CC2)CC1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CC2CCN(c3ccc(Nc4ncc5ccc(-c6cccc(S(=O)(=O)NC(C)(C)C)c6)n5n4)cc3)CC2)CC1
Yield: 25.4 %

Procedure:
N-tert-Butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (0.1 g, 0.3 mmol), 4-[4-(4-Methyl-piperazin-1-ylmethyl)-piperidin-1-yl]-phenylamine (147 mg, 0.510 mmol), N,N-Diisopropylethylamine (0.124 mL, 0.712 mmol), and 1-Methoxy-2-propanol (0.5 mL, 5 mmol) were heated in the microwave at 225° C. for 30 minutes. The reaction was concentrated and redissolved in 3 ml of DMSO and placed onto the Gilson. The most pure fractions were combined basified with sat. sodium bicarbonate, extracted with DCM, dried filtered and concentrated to give a yellow solid (47 mg, 30%). MP 233-235° C. LCMS (E/I+) 485 (M+H). NMR 1H (DMSO-d6)-9.26 (s, 1H), 8.98 (s, 1H), 8.54 (s, 1H), 8.38 (d, 1H, J=8.04 Hz), 7.84 (d, 1H, J=7.90 Hz), 7.73 (t, 1H, J=7.81 Hz), 7.57-7.61 (m, 3H), 7.16 (d, 1H, J=4.52 Hz), 6.93-6.97 (m, 3H), 3.58 (d, 2H, J=11.59 Hz), 2.54-2.62 (m, 2H), 2.28-2.38 (m, 6H), 2.14 (m, 6H), 1.77 (d, 2H, J=12.50 Hz), 1.55-1.65 (m, 1H), 1.16-1.26 (m, 3H), 1.12 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]([CH3:25])[N:23]=[N:24][C:20]=2[CH:19]=1>>[CH3:25][N:22]1[C:21]2[CH:26]=[CH:27][C:18]([CH2:17][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[N:11]3[CH:15]=[N:14][N:13]=[CH:12]3)=[CH:19][C:20]=2[N:24]=[N:23]1
Reactant: Cn1nnc2cc(CCl)ccc21
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Product: Cn1nnc2cc(CN(c3ccc([N+](=O)[O-])cc3)n3cnnc3)ccc21

Procedure:
Starting Compounds: 4-[(4-nitrophenyl)amino ]-4H-1,2,4-triazole and 5-chloromethyl-1-methyl-1H-benzotriazole
Reaction SMILES: FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.[NH2:16][CH2:17][C:18]1[C:19]([Cl:28])=[C:20]([C:24]([F:27])=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22].[C:29](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30]>C1COCC1>[Cl:28][C:19]1[C:18]([CH2:17][NH:16][C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[CH:26][CH:25]=[C:24]([F:27])[C:20]=1[C:21]([OH:23])=[O:22]
Reactant: NCc1ccc(F)c(C(=O)O)c1Cl
Reactant: CC(C)(C)C(=O)Cl
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(F)c(C(=O)O)c1Cl

Procedure:
BSTFA (0.18 mL; 1.15 mmol) was added to a mixture of 3-aminomethyl-2-chlor-6-fluorobenzoic acid (270 mg; 1.12 mmol, HCl-salt) in 8 mL THF, it was stirred at reflux for 20 min, and then cooled in an ice bath. TEA (0.783 mL; 5.62 mmol) and Piv-Cl (142 μL; 1.16 mmol) in 2 mL THF were added and it was stirred overnight. The solvent was removed i.vac. and the residue was diluted with water and 10 mL HOAc, extracted (3×) with DCM, dried over Na2SO4 and concentrated i vac.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:15]=[CH:16][C:3]1=2.C(O)C.[OH-].[K+].Cl>O>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CCOC(=O)C(C)c1ccc2c(c1)Sc1ccccc1CC2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
The mixture of 83 mg of ethyl 2-(10,11-dihydro-11-oxo dibenzo[b,f]thiepin-3-yl)-propionate, 0.8 ml of ethanol, 120 mg of potassium hydroxide and 0.8 ml of water was stirred at room temperature for 2 hours. The solvent was distilled off to obtain the residue, which was acidified with hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain brown oil, which was chromatographed over silica gel, eluted with chloroform to give 59 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]thiepin-3-yl)-propionic acid as pale yellow oil. The result in IR spectrum thereof is in accordance with that of the compound obtained in Example 9.
Reaction SMILES: COC(C1C(C2C=CC([C@H](NC([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=O)C)=C(F)C=2)=CC=CC=1Cl)=O.C(O[C:34](=[O:59])[NH:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[C:48]([Cl:50])[CH:47]=[C:46]([F:51])[C:45]=2[C:52]2[N:53]=[N:54][N:55]([CH3:57])[N:56]=2)=[CH:40][C:39]=1[F:58])[CH3:37])(C)(C)C>>[Cl:50][C:48]1[CH:47]=[C:46]([F:51])[C:45]([C:52]2[N:53]=[N:54][N:55]([CH3:57])[N:56]=2)=[C:44]([C:41]2[CH:42]=[CH:43][C:38]([C@H:36]([NH:35][C:34]([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=[O:59])[CH3:37])=[C:39]([F:58])[CH:40]=2)[CH:49]=1
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Product: C[C@@H](NC(=O)C1(N)COC1)c1ccc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F

Procedure:
The title compound was prepared in analogy to intermediate 4 using a modified procedure in step A for the synthesis of {(R)-1-[5′-chloro-3,3′-difluoro-2′-(2-methyl-2H-tetrazol-5-yl)-biphenyl-4-yl]-ethyl}-carbamic acid tert-butyl ester:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:9]=2[N:10]=1.[H][H]>[Pd].CCO.C1COCC1>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Yield: 79.5 %

Procedure:
Combine N,N,N′-Trimethyl-N′-(6-nitro-benzothiazol-2-yl)ethane-1,2-diamine (5.79 g, 20.6 mmol) and 5% palladium on carbon (5.02 g) in EtOH (200 mL) and THF (25 mL). Shake on a Parr shaker at 60 psi of hydrogen at room temperature for 18 h. Filter the reaction mixture through filter paper, wash with EtOH (50 mL), and concentrate in vacuo to afford the crude title compound (4.1 g, 80%). The crude product was carried on as is. 1H NMR (400 MHz, DMSO-d6): δ 7.10 (d, 1H, J=8.4 Hz), 6.86 (d, 1H, J=1.8 Hz), 6.52 (dd, 1H, J=8.4, 2.2 Hz), 4.80 (br s, 2H), 3.51 (t, 2H, J=6.6 Hz), 3.04 (s, 3H), 2.48 (m, 2H), 2.18 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][O:17][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COC(c1ccc(N)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), 2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g), PPh3 (1.56 g) and molecular sieves 4 Å in THF (100 mL) was added DEAD (0.93 mL) slowly. The reaction was stirred at RT for 5 h and at reflux for overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken into ether. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a crude product as a very viscous brown oil which was chromatographed through silica gel (400 g, 2:1:7 to 3:1:6 EtOAc/Et3N/hexanes) to afford 2-[1-(4-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:15][O:16][C:17](=[O:41])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36](Cl)(=[O:38])=[O:37])=[C:20]1[CH3:40]>ClCCl>[CH3:15][O:16][C:17](=[O:41])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36](=[O:38])(=[O:37])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:20]1[CH3:40]
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Nc2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of aniline (0.022 mL), triethylamine (0.051 mL) and dichloromethane (0.5 mL) was treated with [3-(2-chlorosulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.10 g), and resulting mixture was stirred at room temperature for 4 days. The mixture was diluted with dichloromethane, washed with water and concentrated under reduced pressure to afford the title compound as a colourless gum (0.078 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]([CH3:17])[C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:22])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]([C:14]([Cl:22])=[O:15])=[CH:12][N:11]([CH3:17])[C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1C=C(C(=O)O)[C@H](c2ccc(F)cc2)NC1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C=C(C(=O)Cl)[C@H](c2ccc(F)cc2)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10 mL dichloromethane and 1 drop of DMF was added 150 mg of (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid. To this mixture was added 70 μl oxalyl chloride. When the bubbling stopped another drop of oxalyl chloride was added but as no bubbling was observed the solution was stirred at room temperature for 30 minutes after which the solvent was removed in vacuo to afford crude (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid chloride (not shown in Scheme H). This acid chloride was taken up in propionitrile and added to a solution of 125 mg 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine, 3 ml propionitrile, and 0.1 ml di-iso-propylethylamine. The solution was stirred at room temperature for 18 hours, then diluted with ethyl acetate and aqueous pH 2 buffer. The layers were separated and the organic layer dried over Na2SO4, filtered and the solvent removed in vacuo to give (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid{5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-amide, which was used directly in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH2:34]1[O:36][CH2:35]1>C1C=CC=CC=1>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][OH:36])[C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C1CO1
Reactant: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2)cc1OC
Solvent: c1ccccc1
Solvent: CO
Product: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2CCO)cc1OC
Yield: 97.7 %

Procedure:
50 g of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-piperazine (cf. Example 2) are dissolved in 200 ml of benzene and 400 ml of methanol and heated for 48 hours in a pressure vessel at 60° C. with addition of 22 g of ethylene oxide. Subsequently, the solution is evaporated to dryness. The residue is dissolved in 500 ml of diethylether, combined with 60 ml of 2N HCl, and vigorously stirred. The organic phase is separated and washed halide-free with water. The aqueous acid extract is alkalized with ammonium hydroxide solution and extracted with diethyl ether. The extract is dried, filtered, and the solvent is removed by distillation. 54 g (98 percent of theory) of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-hydroxyethylpiperazine are obtained as a colorless resin.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[H-].[Na+].S([O-])(=O)(=O)C>CN(C=O)C>[N:19]1([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cncn2)CC1
Temperature: 60 °C
Reaction time: 120 h

Procedure:
To a stirred solution of: tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (5.9 g, 21.1 mmol) and 1,2,4-triazole (1.75 g, 1.2 equiv.) in DMF at ambient temperature was added sodium hydride (60% in mineral oil, 1.0 g, 1.2 equiv.). The mixture was stirred at 60° C. for 5 days, and the TLC showed no starting mesylate left. The mixture was poured into ice water and extracted with ethyl acetate (3×). The organic layer was dried, evaporated and purified by silica flash column eluting with 0-10% methanol in ethyl acetate to give tert-butyl 4-(1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate as a white solid. The solid was then treated with hydrogen chloride in dioxane (4 N, 10 mL) for 2 hours. The mixture was then evaporated to remove most of the dioxane to give a white solid, which was washed with ethyl acetate to give the desired 4-(1H-1,2,4-triazol-1-yl)piperidine hydrochloride salt (5.55 g). 1H NMR (300 Mz, CD3OD): 10.00 (s, 1H), 8.97 (s, 1H), 5.10-5.00 (m, 1H), 3.63-3.58 (br. d, 2H), 3.33-3.26 (br. d, 2H), 2.50-2.30 (m, 4H).
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[C:16]([C:22]([OH:24])=[O:23])=[N:15]2)=[CH:10][CH:9]=1>O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[C:16]([C:22]([O:24][CH3:1])=[O:23])=[N:15]2)=[CH:10][CH:9]=1
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Reactant: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nn(-c2ccc(Cl)cc2)c(C)cc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 100 ml of methanol, cooled to -5° C., there is added dropwise 11.9 g (0.1 mol) of thionyl chloride. Upon completion of the addition 13.23 g (0.05 mol) of 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic Acid (see Example 12) is added. The suspension formed is vacuum filtered after stirring at room temperature for 3 hrs. to afford the product, mp 183°-193° C. decomp. Treatment of the product with water affords the Methyl 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15](OCC)(=[O:18])[NH:16][NH2:17]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:15](=[O:18])[NH:16][N:17]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Br)cc2)nn1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: O=c1[nH]nc2ccc(-c3ccc(Br)cc3)nn12

Procedure:
A mixture of 2.69 g. of 6-(p-bromophenyl)-3-chloropyridazine (U.S. Pat. No. 4,092,311), 3.12 g. of ethyl carbazate and 50 ml. of n-butanol is heated at reflux for 16 hours, then cooled and filtered giving an orange solid which is saved. The filtrate is heated at reflux for 23 hours, then chilled in an ice bath and filtered giving more orange solid. The two crops are combined and recrystallized from dimethylformamide, giving 0.65 g. of the desired product as orange crystals, m.p. 348°-350° C. (dec.).
Reaction SMILES: [I-].[I-].[CH3:3][N+:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][C:13]2[CH:30]=[CH:29][C:28]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32](C4C=[N+](C)C=CC=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:14]=2)=[O:11])[CH:5]=1.C1([CH2:47][N:48]2[CH:53]=[CH:52][C:51](C(N)=O)=[CH:50][CH2:49]2)C=CC=CC=1>C(#N)C.C(Cl)Cl>[CH3:3][N:4]1[CH:9]=[CH:8][CH2:7][C:6]([C:10]([O:12][C:13]2[C:14]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32]([C:52]4[CH2:51][CH:50]=[CH:49][N:48]([CH3:47])[CH:53]=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:28]=[CH:29][CH:30]=2)=[O:11])=[CH:5]1
Reactant: C[n+]1cccc(C(=O)Oc2ccc3c(c2)CC[C@@H]2[C@@H]3CC[C@]3(C)[C@@H](OC(=O)c4ccc[n+](C)c4)CC[C@@H]23)c1
Reactant: NC(=O)C1=CCN(Cc2ccccc2)C=C1
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Product: CN1C=CCC(C(=O)Oc2cccc3c2[C@H]2CC[C@]4(C)[C@@H](OC(=O)C5=CN(C)C=CC5)CC[C@H]4[C@@H]2CC3)=C1
Temperature: 0 °C

Procedure:
One gram (1.31 mmol) of the product of Example 71 was dissolved in 100 mL of dry acetonitrile. To that solution, which was flushed with nitrogen, 0.28 g (1.31 mmol) of 1-(phenylmethyl)-4-(aminocarbonyl)-1,2-dihydropyridine was added, and the reaction mixture was stirred at 0° C. for l hour. Removal of the solvent under reduced pressure afforded a solid, which was suspended in methylene chloride and removed by filtration. The filtrate was chromatographed several times on a neutral alumina column prepared with methylene chloride. Purification and evaporation of the solvent in vacuo gave a solid foam. The product had the formula ##STR106## as confirmed by UV, NMR and elemental analyses.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]2([CH:12]([CH3:15])[CH:13]=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.C(=O)([O-])[O-].[K+].[K+]>C(O)COCCO>[C:1]1([S:7][CH2:8][C:9]2([CH:12]([CH3:15])[CH3:13])[CH2:10][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C=O)C1(CSc2ccccc2)CC1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: CC(C)C1(CSc2ccccc2)CC1
Temperature: 150 °C
Yield: 101.8 %

Procedure:
A mixture of 14 (2.12 g, 8.62 mmol), hydrazine hydrate (55% in water, 7.4 mL, 131 mmol) and potassium carbonate (3.2 g, 23.2 mmol) in diethylene glycol (21 mL) was heated at 150° C. (bath temperature) for 3 hr. After cooled to ambient temperature, the mixture was poured into ice water and extracted with n-hexane. The combined organic layers were washed with cold diluted hydrochloric acid, water, sodium bicarbonate solution and brine, and dried over sodium sulfate. Filtration and concentration gave 1.81 g of an oily material, which was purified by column chromatography (silica gel 20 g, 1-2% ethyl acetate in n-hexane) to give 1.69 g (85.1%) of 15, as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:11][C:12]([F:29])([C:25]([F:28])([F:27])[F:26])[C:13]([N:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[O:14]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:14][C:13]([C:12]([F:11])([F:29])[C:25]([F:26])([F:27])[F:28])=[N:15][C:16]([C:17]([F:18])([F:20])[F:19])([C:21]([F:24])([F:23])[F:22])[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(N=C(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: COc1cccc(C#N)c1
Solvent: CCOCC
Product: COc1cccc(C2=NC(C(F)(F)F)(C(F)(F)F)N=C(C(F)(F)C(F)(F)F)O2)c1
Temperature: 60 °C
Yield: 8127 %

Procedure:
3-Methoxybenzonitrile (1.31 g. 0.01 mole) and 2,2,3,3,3-pentafluoro-N-{2,2,2-trifluoro-1-(trifluoromethyl)ethylidene}propanamide (4.67 g., 0.015 mole) were dissolved in diethyl ether and heated in a glass ampoule to 60° C. for six hours. Solvent was evaporated off and the residue distilled at 119° to 120° C./13 min to give a colorless oil (361 g, 82 percent). PMR (CDCl3), 3.85 s (3H), 7.18 d (1H), 7.40 t (1H), 7.55 s (1H), 7.65 d (1H), 19F NMR, −45.74 (2F), −5.47 (3F), −1.12 (6F).