Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH:2]1([CH2:6][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:36][N:37]([CH3:57])[C:38]([C:40]1[N:41]=[C:42]([C@H:45]([CH2:54][CH:55]=O)[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[O:43][CH:44]=1)=[O:39].O>O1CCCC1.C1(C)C=CC=CC=1>[CH:2]1(/[CH:6]=[CH:55]\[CH2:54][C@@H:45]([C:42]2[O:43][CH:44]=[C:40]([C:38]([N:37]([CH3:57])[CH3:36])=[O:39])[N:41]=2)[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(=O)c1coc([C@H](CC=O)CC(=O)OC(C)(C)C)n1
Reactant: c1ccc([P+](CC2CCC2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1coc([C@H](C/C=C\C2CCC2)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A suspension of (cyclobutylmethyl)(triphenyl)phosphonium bromide (Preparation 122) (680 mg, 1.65 mmol) in anhydrous tetrahydrofuran (13 ml), under a nitrogen atmosphere, at 0° C., was treated with sodium bis(trimethylsilyl)amide 1M in tetrahydrofuran (1.65 ml, 1.65 mmol) over a period of 5 minutes. The bright orange mixture was stirred at 0° C. for 1 hour. A solution of tert-butyl (3R)-3-{4-[(dimethylamino)carbonyl]-1,3-oxazol-2-yl}-5-oxopentanoate (Preparation 118) (428 mg, 1.38 mmol) in toluene (4 ml) was added to the mixture and stirred at 0° C. for 30 minutes and allowed to warm to room temperature for a further 30 minutes. Water (2 ml) was added and the solvents were removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with dilute aqueous of potassium sodium tartrate solution and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a solvent gradient of 9:1 (hexane:ethyl acetate) gradually changing to 1:1 (hexane:ethyl acetate) to afford the title compound as a colourless oil (282 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:22](=[O:23])[N:21]([CH3:24])[C:14]3[N:15]=[C:16](SC)[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.O[O:26][S:27]([O-:29])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].CO.Cl[CH2:42]Cl>O.O.C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[C:22](=[O:23])[N:21]([CH3:24])[C:14]3[N:15]=[C:16]([S:27]([CH3:42])(=[O:29])=[O:26])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(-c2cc3cnc(SC)nc3n(C)c2=O)c1
Reactant: O=S([O-])OO
Reactant: ClCCl
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(OC)cc(-c2cc3cnc(S(C)(=O)=O)nc3n(C)c2=O)c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of 6-(3,5-dimethoxyphenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1.05 g, 3.1 mmol) in methanol/dichloromethane (MeOH/DCM) (20 mL/20 mL) was added a solution of Oxone® (potassium peroxymonosulfate) (11.3 g, 18.4 mmol) in H2O (20 mL) at room temperature, and the reaction mixture was stirred at 40° C. for 18 hours. The reaction was monitored by LCMS. The reaction mixture was diluted with H2O/DCM (150 mL/100 mL), and the aqueous phase was extracted with DCM (100 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was recrystallizated with EtOAc to afford 6-(3,5-dimethoxyphenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (8) (910 mg, yield 78%) as yellow solid. MS (ES+) C17H17N3O5S, requires: 375. found: 376 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([O:33]CC)=[O:32].[OH-].[Na+].Cl.CCOC(C)=O>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
Ethyl 6-chloro-7-(4-(4-chlorophenethylcarbamoyl) phenoxy)chroman-4-carboxylate (128.8 g, 250.4 mmol) was dissolved in EtOH (250 mL) and THF (500 mL). NaOH (6N) (62.60 ml, 375.6 mmol) was added and the mixture was stirred at ambient temperature for 1.5 hours. The mixture was transferred to a 2 L separatory funnel and 1N HCl (500.8 ml, 500.8 mmol) was added to the mixture. Additional EtOAc (250 ml) was added and the layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude solid was recrystallized from THF and hexanes to provide 122.0 g of the title compound as a faint pink solid (yield 95.0%). 1H NMR analysis showed that the solid contained THF. The THF content was 27 mol % (5.2% weight) and the desired product content by weight was 94.8%. MS (apci) m/z=486.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([C:29](=[O:36])[C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2I)[CH:15]=1>>[CH3:11][O:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:30](=[C:31](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:32]([CH3:35])([CH3:34])[CH3:33])/[C:29]2=[O:36])[CH:15]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)(C)C)c2ccccc2I)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(Cl)cc3)C(C)(C)C)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-chlorophenylboronic acid (commercially available) and 3-{[(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (400 MHz, DMSO-d6) δppm 1.36 (s, 9H) 3.84 (s, 3H) 5.07 (s, 2H) 5.30 (d, J=7.83 Hz, 1H) 6.57 (t, J=7.83 Hz, 1H) 6.88 (d, J=7.83 Hz, 1H) 7.05 (t, J=7.71 Hz, 1H) 7.21 (d, J=8.08 Hz, 2H) 7.51 (t, J=7.71 Hz, 1H) 7.57-7.64 (m, 2H) 7.87 (d, J=7.58 Hz, 1H) 7.97 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[CH2:34](O)[CH2:35][OH:36].O.Cl>CN(C)C1C=CN=CC=1.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([O:31][CH2:34][CH2:35][OH:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: OCCO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)OCCO)c[nH]4)c3)cc2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (50 mg, 0.11 mmol), ethylene glycol (1 ml), 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCl, 25 mg, 0.13 mmol) and 4-dimethylaminopyridine (DMAP, 5 mg, 0.04 mmol) in anhydrous THF (10 ml) was stirred at 60° C. for 16 hours. The mixture was poured into 100 ml of water. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography with a gradient of 3-5% MeOH/CHCl3 to give 2-hydroxyethyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 36 mg, 67%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(N(CC)CC)C.[O:17]=[C:18]1[C:26]([C:27]#[N:28])=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([C:35]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[O:36])[CH2:31][CH2:30]2)[C:24]2[C:20](=[CH:21][S:22][CH:23]=2)[NH:19]1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[O:17]=[C:18]1[C:26]([C:27]#[N:28])=[C:25]([N:29]2[CH2:30][CH2:31][N:32]([C:35]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[O:36])[CH2:33][CH2:34]2)[C:24]2[C:20](=[CH:21][S:22][CH:23]=2)[N:19]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OB(O)c1cccnc1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2n(-c2cccnc2)c1=O
Temperature: 25 °C

Procedure:
Cu(OAc)2 (363 mg, 2 mmol), pyridine-3-boronic acid (614 mg, 5 mmol), and triethylamine (560 μL, 4 mmol) were added to a solution of 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile (47) (370 mg, 1 mmol) in wet DMF (DMF:H2O::9:1) stirred at room temperature. The solution was further stirred at room temperature for 24 h. The solution was passed through a bed of celite and the solvent was evaporated. The residue was suspended in water and extracted by CH2Cl2. The combined organic phase was partitioned with 10% aqueous HCl solution. The aqueous phase was separated and the pH was adjusted to 5 by 4 N NaOH solution. Then, a saturated solution of NaHCO3 was added until the pH reached to 8. The solids formed were filtered, washed by water, and dried under vacuum at 70° C. to get 5-oxo-4-pyridine-3-yl-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile as white solids. Yield 243 mg (54%); MP 282° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.99 (m, 8H), 6.42 (d, J=2.8 Hz, 1H), 7.18 (dd, J=4.0, 4.8 Hz, 1H), 7.52 (d, J=2.8 Hz, 1H), 7.64 (dd, J=4.8, 8.0 Hz, 1H), 7.81 (d, J=4.8 Hz, 1H), 7.88 (dm, 1H), 8.47 (d, J=3.2 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.71 (d, J=3.6 Hz, 1H) ppm; MS m/z=448 amu (M++1). Anal. (C22H17N5O2S2) N.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C.CC(O)C>O>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: NCc1ccccn1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.1 %

Procedure:
A mixture of 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (0.82 g, 2.92 mmol), 2-(aminomethyl)pyridine (0.35 g, 3.21 mmol), triethylamine (0.32 g, 0.45 ml, 3.21 mmol) and propan-2-ol (20 ml) was stirred at ambient temperature for 72 hours. Water (50 ml) was added to the reaction mixture and the organic phase was extracted using dichloromethane (3×50 ml). The combined extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give 2-chloro-N-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (1.0 g) as a white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=1.[CH3:23][C:24]1[C:29]([CH2:30][C:31](O)=[O:32])=[CH:28][CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[N:25]=1.ClC1C=CC=CC=1C1N=NC(NNC(=O)CC2C=CC(C(F)(F)F)=CC=2)=CC=1C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH:15][C:31](=[O:32])[CH2:30][C:29]2[C:24]([CH3:23])=[N:25][C:26]([C:34]([F:35])([F:37])[F:36])=[CH:27][CH:28]=2)=[N:12][CH:13]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CC(=O)O
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Agent: O=C(Cc1ccc(C(F)(F)F)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Product: Cc1nc(C(F)(F)F)ccc1CC(=O)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Yield: 100.4 %

Procedure:
The title compound (80 mg, 99%) as a white solid was prepared from 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (50 mg, 0.15 mmol) and 2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetic acid (49.3 mg, 0.225 mmol) in a manner analogous to that in which N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetohydrazide (Example 11A) was prepared. HPLC/MS: retention time=3.63 min, [M+H]+=531.1.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:48])[C@H:11]([CH2:44][CH2:45][S:46][CH3:47])[NH:12][C:13](=[O:43])[CH2:14][N:15]([CH2:27][C@@H:28]([NH:33][C:34](=[O:42])[C@@H:35]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]1[CH3:41])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.[Li+].[OH-].Cl>CO>[CH3:41][N:36]1[C:37](=[O:40])[CH2:38][CH2:39][C@H:35]1[C:34]([NH:33][C@@H:28]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:27][N:15]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH2:14][C:13]([NH:12][C@H:11]([C:10]([OH:48])=[O:9])[CH2:44][CH2:45][S:46][CH3:47])=[O:43])=[O:42]
Reactant: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)[C@@H]1CCC(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)O)Cc1cccc2ccccc12)NC(=O)[C@@H]1CCC(=O)N1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[2(S)-((N-Methylpyroglutamyl)-amino)-3(S)-methylpentyl]-N-(1-naphthylmethyl)-glycyl-methionine methyl ester trifluoroacetate salt (prepared in Example 25, 112 mg, 0.19 mmol) was dissolved in methanol (5 ml) and treated with 0.76 ml of 1N LiOH. The mixture was stirred for 4 hours at room temperature, then treated with 0.76 ml of 1N HCl. The solvent was evacuated in vacuo. The crude product was purified by preparative HPLC (Waters PrepPak C-18 eluting with CH3CN/0.1% TFA in H2O) to give, after lyophilization, the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([NH:23][NH2:24])=[O:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Cl.[C:31](=N)(OCC)[CH3:32]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]=[C:13]([C:18]4[CH:27]=[CH:26][CH:25]=[C:20]([C:21]5[O:22][C:31]([CH3:32])=[N:24][N:23]=5)[CH:19]=4)[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NNC(=O)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1nnc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)o1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 45.3 %

Procedure:
A mixture of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoic acid hydrazide (Starting material 8a-2) (58 mg, 0.15 mmol) and ethyl acetimidate hydrochloride (74 mg, 0.6 mmol) in pyridine (0.6 mL) was heated to 100° C. for 2 h. The mixture was cooled to 23° C., diluted with H2O (30 mL) and stirred for 20 min. The precipitate was collected by filtration, and the crude product was purified by chromatography on silica gel using ethyl acetate/hexane (2:1) as eluent. The purified product was crystallized from Et2O/hexane to give the title compound as light yellow solid (28 mg).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:29])([F:28])[F:27])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][C:31]1([CH3:43])[O:35][C@H:34]([CH2:36][N:37]2[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]2)[CH2:33][O:32]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:28])([F:27])[F:29])[CH:13]=[N:12]2)[C:8]([NH:42][C:39]2[CH:40]=[CH:41][N:37]([CH2:36][C@@H:34]3[CH2:33][O:32][C:31]([CH3:43])([CH3:30])[O:35]3)[N:38]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2OC(F)(F)F)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4ccccc4OC(F)(F)F)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethoxy-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 76) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethoxy-phenoxy)-6H-pyridazin-1-yl]-propionamide as an off-white foam as a mixture of diastereomers (1.37 g, 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COCCNCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCN(CCOC)C(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 76.6 %

Procedure:
To a slurry of 212.0 g of 2,4-dinitrobenzoic acid in 900 ml of toluene were added with stirring 101.0 g of triethylamine, followed by 159.6 g of bis(2- methoxyethyl)amine. Next 75.7 g of phosphorus oxychloride was added dropwise at such a rate to maintain the reaction temperature below 90° C. The mixture was refluxed for 5 hrs, cooled to 80° C., and poured slowly into 1000 ml of aqueous 5% NaHCO3 solution with stirring. The precipitate was filtered, washed with water and recrystallized from hot methanol to yield 250.7 g of N,N-bis(2-methoxyethyl)-2,4-dinitrobenzamide, mp 89° C. An additional 19.0 g of material was recovered from the toluene filtrate.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:5]=1)([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([CH2:15][O:14][C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:13]=[CH:12][C:7]=2[C:8]([OH:10])=[O:9])[CH2:17]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(C(C)C)cc1OCC1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(=O)O)c(OCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 65 °C
Yield: 83.6 %

Procedure:
The methyl 4-isopropyl-2-(1-tert-butoxycarbonyl-piperidin-3-ylmethoxy)benzoate (1.53 g, 3.90 mmol) was dissolved in THF (15 mL). Then LiOH.H2O (0.36 g, 8.58 mmol) in water (5 mL) was added. The mixture was heated at 65° C. for 24 h. The reaction mixture was concentrated in vacuo and then redissolved in a mixture of EtOAc (100 mL) and cold dilute HCl. The mixture was shaken in a separatory funnel. The layers were separated and the organic layer was washed with cold water (100 mL), dried (MgSO4), and concentrated to give 1.23 g of the title compound as an oil.
Reaction SMILES: [F:1][CH:2]([F:11])[S:3][CH2:4][C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[F:1][CH:2]([F:11])[S:3][CH2:4][C:5](=[N:13][OH:14])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)CSC(F)F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(CSC(F)F)=NO

Procedure:
A mixture of 1-difluoromethylthio-3,3-dimethyl-2-butanone (2.21 moles) from example 1, hydroxylamine hydrochloride (2.44 moles) and sodium carbonate (1.22 moles) in aqueous ethanol (1 liter of water and 2.3 liters of ethanol) was heated at its reflux temperature for 7.5 hours. This reaction mixture was poured into water, and the product was extracted into diethyl ether. The ether was washed with water and dried, then the ether extracts were evaporated under reduced pressure leaving a residue of 1-difluoromethylthio-3,3-dimethyl-2-butanone oxime. A pure sample, m.p. 92° to 95°C., was obtained by recrystallization from a mixture of diethyl ether and petroleum ether (b.p. 30° to 60°C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:13]([CH3:18])=[C:14]([F:17])[C:15]=1[F:16])[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:20]([O-])([O-])[O:21][CH2:22][CH3:23]>>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:13]([CH3:18])=[C:14]([F:17])[C:15]=1[F:16])[C:5]([C:7](=[CH:20][O:21][CH2:22][CH3:23])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC(=O)CC(=O)c1c(C)c(F)c(F)c(Cl)c1F
Reactant: CCOC([O-])[O-]
Product: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(Cl)c1F
Yield: 100.8 %

Procedure:
Employing ethyl 3-chloro-2,4,5-trifluoro-6-methylbenzoylacetate (300 mg) and ethyl orthoformate (550 mg), the procedure of Reference Example 20 is repeated to give ethyl 2-(3-chloro-2,4,5-trifluoro-6-methylbenzoyl)-3-ethoxyacrylate (360 mg), as brown oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.[C:26]([N:28]=[C:29](SC)[S:30][CH3:31])#[N:27].CCN(CC)CC>CC#N>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:29](=[N:28][C:26]#[N:27])[S:30][CH3:31])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Reactant: CSC(=NC#N)SC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSC(=NC#N)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 57.8 %

Procedure:
A 25 mL flask was charged with (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (3 g, 8.15 mmol) and dimethyl cyanocarbonimidodithioate (1.2 g, 8.15 mmol) dissolved in 50 mL of MeCN, and 1 mL Et3N was added and the mixture was stirred for overnight. The mixture was evaporated in vacuo and the residue was purified by chromatography to give desired (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-((cyanoimino)(methylthio)methylamino)ethoxy)methyl)-piperidine-1-carboxylate (2.2 g, 58%). 1H NMR (CDCl3, 400 MHz) δ 7.28 (m, 2H), 7.23 (m, 1H), 7.16 (m, 1H), 4.10 (m, 2H), 3.86 (m, 1H), 3.68 (m, 2H), 3.22 (m, 2H), 2.72 (m, 2H), 1.62 (m, 2H), 1.46 (s, 9H), 1.40-1.10 (m, 4H).
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:24][CH2:25][C@H:26]([CH3:29])[CH2:27][OH:28].O>C1COCC1>[Br:24][CH2:25][C@H:26]([CH3:29])[CH2:27][O:28][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H](CO)CBr
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CBr)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyldiphenylchlorosilane (83 mL) and imidazole (30 g) were added to a solution of (R)-3-bromo-2-methyl-1-propanol (45 g) in THF (150 mL) under ice-cooling, and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 117 g of the title compound. The property values of the compound are as follows.