Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([N+:18]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl>CO.[Fe]>[NH2:18][C:9]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:11][C:2]([CH3:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(-c2ccccc2)cc1C
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(N)c(-c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
13 g of methyl 2-methyl-5-nitro-4-phenylbenzoate were dissolved in 150 ml of MeOH and treated with 10 g of iron powder. A saturated aqueous HCl solution was then slowly added dropwise and the mixture was stirred at RT for 2 hours. The volatile components are removed in vacuo at a maximum temperature of 30° C., 500 ml of a saturated aqueous Na2CO3 solution were added, the iron salts were filtered off and the filtrate was extracted 3 times using 500 ml of EA each time. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo. 10 g of colorless oil were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](/[N:11]=[CH:12]/[N:13]([CH3:15])[CH3:14])(=[O:10])=[O:9].[CH3:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CCO.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.O>[CH3:14][N:13]([CH3:15])/[CH:12]=[N:11]/[S:8]([C:3]1[C:2]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CN(C)/C=N/S(=O)(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccccc2S(=O)(=O)/N=C/N(C)C)cc1
Temperature: 70 °C
Yield: 82.7 %

Procedure:
2-Bromo-N-[1-dimethylaminometh-(E)-ylidene]-benzenesulfonamide (5.4 g, 18.4 mmol), 4-methylphenylboronic acid (5.0 g, 36.8 mmol) and potassium carbonate (5.1 g, 36.8 mmol) were dissolved in water (19.7 mL, 1090 mmol), EtOH (49.2 mL, 842 mmol) and toluene (98.3 mL, 923 mmol). The resulting mixture was stirred under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol) was added. The mixture was heated at 60° C. for 115 minutes, at 70° C. for 30 minutes, then cooled to room temperature. Water (100 mL) and EtOAc (100 mL) were added. The mixture was washed with saturated aqueous NaCl, extracted with EtOAc, dried over MgSO4, filtered, and concentrated to yield a red solid. The product was triturated with 1:1 EtOAc:hexanes, filtered, and rinsed with hexanes to yield a reddish-brown solid. The product was triturated with EtOAc, filtered, and rinsing with EtOAc. to yield 4′-methylbiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide (4.6 g) as a light brown solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[N:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O.C1(C)C=CC=CC=1>CCO>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:8]1[N:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: OB(O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccnc1-c1ccc(F)cc1F
Temperature: 82 °C
Reaction time: 8 h

Procedure:
To a nitrogen purged 3.0 L, 4-necked flask, fitted with an overhead stirrer, thermocouple, heating mantle, nitrogen outlet and reflux condenser, was charged Pd(Ph3)4 (5.0 g, 4.33 mmoles, 0.005 eq), sodium carbonate (92.6 g, 874 mmoles, 1.3 eq), ethyl 2-chloronicotinate, 1 (126.0 g, 678 moles, 1.0 eq), 2,4-difluorophenylboronic acid, 2 (125 g, 791 mmoles, 1.2 eq), followed by 0.5 L of toluene and 125 mL denatured EtOH. The reaction was heated to 82° C. with vigorous stirring under N2 overnight (completeness of reaction determined by HPLC and TLC). The reaction was cooled to room temperature, the mixture filtered through a small pad of Celite® and the solvents removed under vacuum at 55° C. The residue was dissolved in EtOAc, washed, dried (MgSO4), filtered through Celite® again, and concentrated. The product was obtained as a yellow solid.
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.[C:51](Cl)(=[O:58])[C:52]1[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=1>ClCCl.C(N(CC)CC)C>[C:51]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[N:28]=[C:23]([N:17]3[CH2:16][CH:15]4[O:22][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:24]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[O:43])=[CH:39][CH:40]=3)[N:26]=2)[CH2:30][CH2:31]1)(=[O:58])[C:52]1[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCN(C(=O)c4ccncc4)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (100 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treated with isonicotinoyl chloride (100 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 593.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])[CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=4)=[CH:24][C:25](=[O:26])[NH:14][C:5]=23)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(=O)c1cccc(OC)c1
Reactant: Cc1ccc(-c2c(C)n[nH]c2N)cc1
Solvent: c1ccncc1
Product: COc1cccc(-c2cc(=O)[nH]c3c(-c4ccc(C)cc4)c(C)nn23)c1
Temperature: 25 °C

Procedure:
3-Methyl-4-(4-methylphenyl)-1H-pyrazol-5-amine and ethyl 3-(3-methoxyphenyl)-3-oxopropanoate are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and the target compound is yielded by column chromatography.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].FC(F)(F)C(O)=O.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:18]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]2[C:26](=[O:28])[CH3:27])[CH:19]=1.C(=O)(O)[O-].[Na+]>>[NH2:13][C:14]1[C:15]([N+:1]([O-:4])=[O:2])=[CH:16][C:17]([O:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[C:18]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]2[C:26](=[O:28])[CH3:27])[CH:19]=1
Reactant: CC(=O)N1CCCCC1c1cc(N)ccc1Oc1ccc(F)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCCCC1c1cc(N)c([N+](=O)[O-])cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64 mg of potassium nitrate was added to a trifluoroacetic acid (1 ml) solution of 190 mg of 1-(2-(5-amino-2-(4-fluoro-phenoxy)-phenyl)-piperidin-1-yl)-ethanone, and the reaction liquid was stirred overnight at room temperature. Aqueous saturated sodium bicarbonate was added to the reaction liquid to neutralize it, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25]C(=O)CC4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl.CO>[C:8]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][S:37]([C:40]2[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=2)(=[O:39])=[O:38])=[O:16])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OC(c2ccccc2)c2ccccc2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC2CS[C@@H]3[C@H](N)C(=O)N3C2C(=O)OC(c2ccccc2)c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 4 h

Procedure:
To a solution of 3-p-toluenesulfonyloxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (3d) in dichloromethane (7 parts) cooling at -25° to -20° C. under nitrogen are added pyridine (2 equivalents) and phosphorus pentachloride (1.7 equivalents). After stirring at -15° to -10° C. for 4 hours, the mixture is diluted with methanol (12 parts) cooled at -30° C., stirred at -30° to -25° C. for 30 minutes and at 0° to 5° C. for 2 hours. The reaction mixture is diluted with dichloromethane and ice-water and stirred at 0° to 5° C. for 20 minutes. The formed organic layer is taken, washed with water, dried, and concentrated. The residue is crystallized from dichloromethane-ether mixture to give 3-p-toluenesulfonyloxy-7beta-aminocepham-4-carboxylic acid diphenylmethyl ester (4d) p-toluenesulfonate salt. mp. 190°-194° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>>[CH3:1][C:2]1([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:35])[CH2:4][O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2ccsc2)OCC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Product: CC1(c2ccsc2)OCC(=S)Nc2ccc(-c3ccc(C#N)[nH]3)cc21

Procedure:
Prepared from 5-[5-methyl-2-oxo-5-(3-thienyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-2-carbonitrile and Lawesson's reagent generally according to example 10. 1H NMR (DMSO-d6): δ 12.67 (s, 1H), 12.01 (s, 1H), 7.71-7.74 (m, 2H), 7.54 (dd, J=5.08, 2.99 Hz, 1H), 7.41 (d, J=9.2 Hz, 1H), 7.2 (dd, J=2.87, 1.3 Hz, 1H), 7.05 (dd, J=5.04, 1.31 Hz, 1H), 7.00 (dd, J=3.84, 2.1 Hz, 1H), 6.76 (dd, J=3.79, 2.51 Hz, 1H), 4.4 (d, J=15.34 Hz, 1H), 4.27 (d, J=15.33 Hz, 1H), 1.98 (s, 3H); MS (ESI) m/z 366 ([M+H]+); MS (ESI) m/z 364 ([M−H]−). Anal. calcd for C19H15N3OS2: C, 62.44; H, 4.14; N, 11.5. Found: C, 61.9; H, 4.14; N, 11.27.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])/[CH:31]=[CH:32]/C)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.NC1N=CN=C2N(C3CCCN(S(C=C)(=O)=O)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N(C3CCCN(C(=O)C#C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N(C3CCN(C(=O)C=C)CC3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.C(=O)C=C.NC1N=CN=C2N(C3CCCN(C(=O)/C=C/CN(C)C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[CH:31]=[CH2:32])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: C/C=C/C(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: C#CC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: C=CC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Agent: C=CC=O
Product: C=CC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1

Procedure:
(E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)but-2-en-1-one (Compound 5); 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)sulfonylethene (Compound 6); 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one (Compound 8); 1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 9); N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)acrylamide (Compound 10); 1-(R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 11); 1-(S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 12); 1-(R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 13); 1-(S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 14); and (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Compound 15).
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH2:23][CH3:24])[CH:17]([CH3:22])[C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][C:10]=1[OH:25])C1C=CC=CC=1>[Pd].CO>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH2:23][CH3:24])[CH:17]([CH3:22])[C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][C:10]=1[OH:25]
Reactant: CCC1C(c2ccc(NCc3ccccc3)c(O)c2)=NNC(=O)C1C
Agent: [Pd]
Solvent: CO
Product: CCC1C(c2ccc(N)c(O)c2)=NNC(=O)C1C

Procedure:
2.20 g (6.52 mmol) 6-(4-benzylamino-3-hydroxy-phenyl)-5-ethyl-4-methyl-4,5-dihydro-2H-pyridazin-3-one, 120 mg 10% Pd/C and 20 mL MeOH are hydrogenated for 2 h at 3 bar H2. The reaction mixture is concentrated by rotary evaporation i. V. and the residue is crystallised with acetonitrile/diethyl ether.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([CH2:20][S:21]C(=O)C)[CH2:6][C@H:7]1[CH2:11][C@@H:10]([NH:12]C(OC(C)(C)C)=O)[CH:9]=[CH:8]1)C>Cl>[NH2:12][C@@H:10]1[CH2:11][C@H:7]([CH2:6][CH:5]([CH2:20][SH:21])[C:4]([OH:25])=[O:3])[CH:8]=[CH:9]1
Reactant: CCOC(=O)C(CSC(C)=O)C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Product: N[C@H]1C=C[C@@H](CC(CS)C(=O)O)C1
Temperature: 25 °C

Procedure:
A solution of 2-acetylsulfanylmethyl-3-(cis4-tert-butoxycarbonylamino-cyclopent-2-enyl)-propionic acid ethyl ester (86 mg, 0.23 mmol) in concentrated HCl (5 mL) was refluxed under argon for 1 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to afford a diasteromeric mixture of the title compound as the hydrochloride salt (65 mg).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([NH:17]C(OCC3C=CC=CC=3)=O)=[C:4]2[CH2:3]1>CO.[Pd]>[NH2:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: CN1Cc2c(NC(=O)OCc3ccccc3)ncn2-c2ccccc2C1=O
Agent: [Pd]
Solvent: CO
Product: CN1Cc2c(N)ncn2-c2ccccc2C1=O

Procedure:
34 g (93.8 mmol) of benzyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbamate are hydrogenated at room temperature and normal pressure in 300 ml of methanol in the presence of 4 g of 10 percent palladium/carbon. After removal of the catalyst and evaporation, the residue is recrystallized from ethyl acetate and hexane. There is obtained 3-amino-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 202°-204°.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].C(N(CC)CC)C>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15](=[O:26])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCO)Oc1ccc(Oc2ccccc2)cc1
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of the carbonate prepared in Example 1 (10.0 g, 28.4 mmol) in 75 mL of methylene chloride was added under nitrogen dropwise to a solution of 6-amino-1-hexanol (3.34 g, 28.4 mmol) and triethylamine (19.8 mL, 142 mmol) in 100 mL of methylene chloride at ice-bath temperature. The reaction was stirred at ice bath temperature for approximately eight hours and at room temperature overnight. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 8.1 g of a solid. Recrystallization of the solid from diisopropyl ether gave 6.55 g (70%) of the title compound as a white crystalline solid, mp 72°-75° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7](O)[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1.O=P(Cl)(Cl)[Cl:22]>>[F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([Cl:22])[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Product: COC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F

Procedure:
The Route A below schematically depicts a method whereby the substituted pyridine compounds of this invention may be prepared from compounds which are known in the art. In this route, acetone dicarboxylic acid 1 is cyclized into the corresponding anhydride 2 by reacting it with acetic anhydride. The anhydride 2 is dissolved in methanol and stirred to form the acetone dicarboxylic acid monomethyl ester 3. The monomethyl ester is then reacted with isobutylene in acid and a suitable organic solvent to form t-butyl, methyl acetone dicarboxylate 4. The dicarboxylate 4 is then sequentially reacted with magnesium chloride in a suitable organic solvent and with trifluoroacetic anhydride to form methyl, t-butyl diesterpyrone 5.The pyrone 5 is then reacted with trifluoroacetic acid to form the acid methyl ester pyrone 6. The pyrone 6 is then refluxed in a suitable organic solvent to remove the acid moiety and form the methyl ester pyrone 7. The pyrone 7 is then aminated by addition of methanol and ammonia to form 2,6-bis(trifluoromethyl)-3-methoxycarbonyl-4-hydroxy pyridine 8. Pyridine 8 is then chlorinated with a suitable chlorinating agent such as POCl3 to form 2,6-bis(trifluoromethyl)-3-methoxycarbonyl-4-chloropyridine 9. Pyridine 9 is then hydrogenated using standard laboratory techniques to form 2,6-bis(trifluoromethyl)-3-methoxycarbonyl pyridine 10. The pyridine 10 is then hydrolyzed with a strong base to form 2,6-bis(trifluoromethyl)-3-hydroxycarbonyl pyridine 11. ##STR4##
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>CO>[CH:10]([NH:13][CH2:1][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:9])([CH3:12])[CH3:11]
Reactant: c1ccc(C2CO2)cc1
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NCC(O)c1ccccc1
Yield: 49.6 %

Procedure:
A mixture of 120 g (1 mole) styrene oxide and 59 g (1 mole) of isopropylamine are heated under reflux for 5 hours in 400 ml of methanol. The mixture is dry evaporated and the residue is dissolved in 500 ml of water. The desired free base which has precipitated is filtered and the solution is washed with 100 ml of hexane. The base is recrystallized from hexane, and the crystals are filtered and washed with 50 ml hexane and then dried. 89 g (yield=49%) of 2-isopropylamino-1-phenyl-1-ethanol are obtained. M.P. 90° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7][C:8](=[O:14])OC(C)(C)C.C([O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:38]2[C:46]3[C:41](=[CH:42][C:43](C(O)=O)=[CH:44][CH:45]=3)[C:40]([CH3:50])=[C:39]2[CH3:51])=[CH:33][CH:32]=1)=[O:24])(C)(C)C>>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7][C:8]([C:43]1[CH:42]=[C:41]2[C:46](=[CH:45][CH:44]=1)[N:38]([CH2:37][C:34]1[CH:33]=[CH:32][C:31]([C:26]3[C:25]([C:23]([OH:24])=[O:22])=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:36][CH:35]=1)[C:39]([CH3:51])=[C:40]2[CH3:50])=[O:14]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc(CN)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using tert-butyl 3-(aminomethyl)benzylcarbamate and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 518 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[Br:7].[N+:9]([O-])([OH:11])=[O:10].O>S(=O)(=O)(O)O>[Br:7][C:6]1[NH:5][N:4]=[C:3]([CH3:8])[C:2]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1n[nH]c(Br)c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1n[nH]c(Br)c1[N+](=O)[O-]
Temperature: 9 °C
Reaction time: 0.5 h

Procedure:
6.5 g (0.027 mole) of 4,5-dibromo-3-methylpyrazole was dissolved in 20 ml of concentrated sulfuric acid. The solution was cooled to 9°C and 10 ml of 90% nitric acid was added dropwise. The solution was stirred 30 minutes and then slowly heated to 60°C and kept at that temperature for 30 minutes. The solution was cooled and poured into water. The mixture was extracted with ether and the ether was washed with water. The ether solution, after drying over magnesium sulfate was concentrated in vacuo and gave a white solid (1.5 g). One recrystallization from ethyl acetate gave a solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21])=[C:4]([F:10])[CH:3]=1
Reactant: OCc1ccc(Cl)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (4-chloro-2-fluorophenyl)methanol (4.60 g, 28.6 mmol) in THF (100 mL) was added 1H-imidazole (1.95 g, 28.6 mmol) and tert-butylchlorodimethylsilane (4.32 g, 28.6 mmol) at room temperature. The reaction mixture was stirred for 12 h at RT. The white precipitate was filtered and the filtrate was washed with 0.1 N aqueous HCl. The separated aqueous phase was extracted with diethyl ether (2×40 mL). The combined organic phases were washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica (hexanes) gave (4-chloro-2-fluorobenzyloxy)(tert-butyl)dimethylsilane as colorless oil. 1H NMR (300 MHz, CHLOROFORM-d) 6 ppm 7.31 (1H, t, J=8.1 Hz), 7.01 (1H, d, J=8.3 Hz), 6.91 (1 H, dd, J=9.9, 1.8 Hz), 4.64 (2H, s), 0.73-0.86 (9H, m), −0.06 (6H, s)