Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13]CC3C=CC=CC=3)[CH:8]=2)=[C:4]([F:23])[CH:3]=1.[H][H]>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)=[C:4]([F:23])[CH:3]=1
Reactant: Nc1ccc(Oc2ccnc(NCc3ccccc3)c2)c(F)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
Palladium hydroxide on carbon (10%, 0.050 g) was added to a solution of 4-(4-amino-2-fluorophenoxy)-N-benzylpyridin-2-amine (0.245 g, 0.790 mmol, 1.0 eq) in 5% HCO2H-MeOH (10 mL) under a blanket of hydrogen (from a balloon) at room temperature. The reaction mixture was stirred at room temperature for 12 h, filtered through Celite® and the filtrate concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (YMC ODS-A S10 30×500 mm., 10-90% aqueous MeOH with 0.1% TFA, 30 minute gradient) and the appropriate fractions were concentrated in vacuo. The concentrate was neutralized with saturated aqueous NaHCO3 solution and the mixture was extracted with CHCl3 (3×35 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.045 g, 26%) as a solid. 1H NMR (CD3OD) δ 7.62-7.63 (m, 1H), 6.77-6.82 (m, 1H), 6.38-6.47 (m, 2H), 6.09-6.11 (m, 1H), 5.83-5.84 (m, 1H); MS(ESI+) m/z 220 (M+H)+; HRMS(ESI+) calcd.: 220.0886, found: 220.0877.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:15]
Reactant: NN
Reactant: Clc1ncccc1-c1cccnc1
Solvent: c1ccncc1
Product: NNc1ncccc1-c1cccnc1
Temperature: 110 °C

Procedure:
A 440 mg portion of 2-chloro-3,3'-bipyridine and 0.73 ml of anhydrous hydrazine were dissolved in 15 ml of pyridine and heated at 110° C. for 3 days. The volatiles were removed at reduced pressure, 10 ml of toluene was added and the volatiles again removed. The residue was partitioned between 125 ml of methylene chloride and 25 ml of saturated aqueous sodium carbonate. The organic layer was dried and the solvent removed at reduced pressure, giving an oily solid which was recrystallized from methylene chloride-hexane, giving 2-hydrazino-3,3'-bipyridine as a tan powder, mp 104.5°-107° C.
Reaction SMILES: CCCCCC.C([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.[CH2:21]([O:23][C:24]([C@:26]1([F:33])[C@@H:31]2[C@H:27]1[CH2:28][CH2:29][C:30]2=O)=[O:25])[CH3:22].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=[O:42])=CC=1.[CH2:55]([O:57][CH2:58]C)[CH3:56]>O1CCCC1>[CH2:55]([O:57][C:58]([C:30]1[C@H:31]2[C@@H:27]([CH2:28][CH:29]=1)[C@:26]2([F:33])[C:24]([O:23][CH2:21][CH3:22])=[O:25])=[O:42])[CH3:56]
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2CCC(=O)[C@@H]21
Reactant: CCOCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=CC[C@@H]2[C@H]1[C@@]2(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
245 mL of a 2.66M n-butyl lithium hexane solution was added dropwise to 700 mL of a tetrahydrofuran solution containing 137 mL of hexamethyldisilazane, and the mixture was stirred for 1 hour while being maintained at −63° C. to −54° C. 340 mL of a tetrahydrofuran solution containing 101 g of (1R,5R,6R)-6-fluoro-2-oxo-bicyclo[3.1.0]hexane-6-carboxylate ethyl ester was added dropwise thereto while being maintained at −63° C. to −52° C. 700 mL of a tetrahydrofuran solution containing 213 g of N-phenyl-bis(trifluoromethanesulfonimide) was added an hour later at −63° C. to −45° C. The reaction solution was warmed naturally to room temperature and further stirred for 2.5 hours. The reaction solution was diluted with diethyl ether, washed three times with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=30:1 to 20:1 to 5:1). The obtained 175 g of (1R,5R,6R)-6-fluoro-2-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hex-2-en-6-carboxylate ethyl ester was dissolved in 875 mL of N,N-dimethylformamide and 875 mL of ethanol, and after 95.1 mL of diisopropylethylamine, 8.65 g of triphenylphosphine and 3.70 g of palladium acetate were added, the mixture was stirred for 5.5 hours at room temperature under a carbon monoxide atmosphere. 1N hydrochloric acid was added thereto, and the reaction solution was extracted six times with diethyl ether. The organic layers were combined, washed four times with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=30:1 to 20:1 to 10:1), thereby yielding 92.6 g of (1R,5R,6R)-6-fluorobicyclo[3.1.0]hex-2-en-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: F[C:2](F)(F)[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.ClC1C=C[C:20]([C:21]#N)=[CH:19]N=1.C1(O)CCCC1>>[CH:3]1([O:4][C:5]2[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=2)[CH2:21][CH2:20][CH2:19][CH2:2]1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: OC1CCCC1
Product: CC(N)c1ccc(OC2CCCC2)nc1

Procedure:
The title compound was synthesised according to the 2-step procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine starting from 6-chloronicotinonitrile and cyclopentanol.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[C:18]([CH:34]3[CH2:36][CH2:35]3)=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[CH:11][C:10]=1[CH3:37])([CH3:7])[CH3:6])C.[Li+].[OH-]>C1COCC1.CCO.CCOCC>[CH:34]1([C:18]2[C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[C:10]([CH3:37])[CH:11]=3)=[CH:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:27][CH:28]=3)[N:19]=2)[CH2:36][CH2:35]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(SCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)ccc1OC(C)(C)C(=O)O
Reaction time: 23 h

Procedure:
0.386 g (0.7 mmol) of the above prepared 2-{4-[4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was dissolved in 12 ml of THF/EtOH (1:1), treated at 0° C. with 2.12 ml (2.1 mmol) of 1N LiOH, and kept at ambient temperature for 23 h. The reaction mixture was taken up in ether and washed with aqueous 10% KHSO4 solution and aqueous 10% NaCl solution. The water phases were extracted with ether (2×). The organic phase was dried (Na2SO4) and evaporated. The crude product was precipitated in ether/pentane (RT to 4° C.) and filtered to give 0.289 g of the title compound as white crystals of mp. 127–128° C., dec.
Reaction SMILES: C(O)(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[OH:13][C:14]1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.C1OC1>>[C:5]1([CH2:6][OH:8])([CH2:14][OH:13])[CH2:4][CH2:3][CH2:2][CH2:10][CH2:9]1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: C1CO1
Product: OCC1(CO)CCCCC1

Procedure:
As a thermoplastic resin there was used a 5:4:1 (by mole) of terephthalic acid, bisphenol A-ethylene oxide adduct and linear polyester obtained from cyclohexane dimethanol (Tg: 62° C.; Mn: 4,500; Mw: 10,000). This thermoplastic resin was ground using a jet mill, and then classified using an air classifier to prepare a particulate material having d50 of 6 μm.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:30][CH:31]1[C:51](=[O:52])[N:33]2[C:34]([C:48]([OH:50])=[O:49])=[C:35]([CH2:38][S:39][C:40]3[N:44]([CH2:45][CH2:46][OH:47])[N:43]=[N:42][N:41]=3)[CH2:36][S:37][C@H:32]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:30][CH:31]2[C:51](=[O:52])[N:33]3[C:34]([C:48]([OH:50])=[O:49])=[C:35]([CH2:38][S:39][C:40]4[N:44]([CH2:45][CH2:46][OH:47])[N:43]=[N:42][N:41]=4)[CH2:36][S:37][C@H:32]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCO)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCO)CS[C@H]12)c1csc(NC=O)n1
Yield: 69.2 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.), N,N-dimethylformamide (0.45 g.), phosphoryl chloride (1.0 g.), 7-amino-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (2 g.), trimethylsilylacetamide (5.9 g.) and ethyl acetate (50 ml.) were treated in a similar manner to that of Example 6-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.7 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1.[CH3:17][N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:19].[B-](F)(F)(F)F.CNC>CO>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:18]([CH3:19])[CH3:17])=[O:16])[CH2:12][CH2:13]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1cnccc1N1CCC(C(=O)O)CC1
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CO
Product: CN(C)C(=O)C1CCN(c2ccncc2N)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A microwave vial was charged with 1-(3-amino-4-pyridyl)piperidine-4-carboxylic acid (125 mg, 0.197 mmol), TBTU (200 mg, 0.62 mmol) and N-methylmethanamine (3.5 mL, 2M in MeOH). The tube was sealed and the mixture stirred for 3 h at 120° C. The crude was redissolved in MeOH and loaded into a MeOH pre-washed SCX column, rinsed with MeOH and the product was released with methanolic ammonia. The ammonia extracts were concentrated under reduced pressure to yield 1-(3-aminopyridin-4-yl)-N,N-dimethylpiperidine-4-carboxamide. MS (ES+) 249.2.
Reaction SMILES: I.CS[C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[F:9][C:10]1[CH:28]=[CH:27][C:13]([CH2:14][N:15]2C(=O)O[C:18](=[O:19])[C:17]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:16]23)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C>C(O)C.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:16]3[C:17](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:18](=[O:19])[N:5]3[CH2:6][CH2:7][N:8]=[C:4]23)=[CH:27][CH:28]=1
Reactant: CSC1=NCCN1
Reactant: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2N(Cc2ccc(F)cc2)C2=NCCN12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A charge of 26 kgs. toluene, 2.5 kgs. 2-methylmercaptoimidazoline hydroiodide, 2.4 kgs. N-(p-fluorobenzyl)isatoic anhydride and 1.55 kgs. powdered anhydrous sodium carbonate is refluxed for 18 - 20 hours in a reaction vessel which is vented to a caustic gas washing tower. Any water formed during the reaction is collected in a Dean-Stark separator. The reaction is cooled to 20°C. and 10 kgs. water added. The mixture is stirred for about 30 minutes and the solids collected, washed several times with 2 kg. portions of water, and three times with 0.8 kg. toluene. The solids are then dried at reduced pressure (about 55°C.) to obtain a crude product, m.p. 196°-198°C. The crude is dissolved at 50°C. in a solution of 14 kgs. chloroform and 4 kgs. ethanol and treated in solution with 0.1 kg. decoloring charcoal for about 10 minutes. The charcoal is removed by filtration through a celite bed and solids reprecipitated by concentrating the filtrate to a volume of about 8 liters. This concentrate is cooled to 0°-5°C., the solids collected by filtration, washed with cold ethanol and then diethyl ether, and dried at reduced pressure to obtain 10-(4'-fluorobenzyl)-2,3-dihydro-imidazo[2,1-b]quinazolin-5(10H)-one, m.p. 197°-198°C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18]>C(O)C>[C:17]([C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:23]=[CH:24][CH:25]=1)#[CH:18]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: C#Cc1cccc(N)c1
Solvent: CCO
Product: C#Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Yield: 67.2 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-quinoline-3-carbonitrile, 200 ml ethanol, and 3.82 g (32.6 mmol) 3-ethynylaniline was heated to reflux under N2. Removed heat at 3½ hours and added a solution of saturated sodium bicarbonate until basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane and collected solids. Washed with water and dried in vacuo. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent and dried in vacuo, giving 4.544 g of yellow solid: mass spectrum (electrospray m/e): M+H=315.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]1[CH2:30][CH2:29][C@:28]([CH:34]([CH3:36])[CH3:35])([C:31](O)=[O:32])[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH:34]([C@:28]1([C:31]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:5]=[C:4]([C:14]([F:17])([F:15])[F:16])[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9][CH2:10]2)=[O:32])[CH2:29][CH2:30][C@@H:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:27]1)([CH3:36])[CH3:35]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: Cc1cc(C(F)(F)F)cc(N2CCNCC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)n1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazine (280 mg, 1.1 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (460 mg, 1.7 mmol) in methylene chloride (30 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.60 g, 1.4 mmol), and triethylamine (0.20 g, 2.0 mmol). After being stirred overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to provide the desired product (200 mg, 35.1%). LCMS calculated for C25H37F3N4O3: (M+1) 499.3; found 499.2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([CH:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1>>[ClH:1].[C:13]([CH:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:26]3[C:25]([CH3:24])=[CH:29][C:28]([CH3:30])=[N:27]3)[N:11]=2)[CH2:21][CH2:22]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Reactant: CC(C)(C)C1CCC(N)CC1
Product: Cc1cc(C)n(-c2nc(NC3CCC(C(C)(C)C)CC3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, 4-tert-butylcyclohexylamine and 3,5-dimethylpyrazole. Mp. 253-255° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.[CH3:25][N:26]=[C:27]=[O:28]>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]([C:27](=[O:28])[NH:26][CH3:25])[CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: CN=C=O
Reactant: COc1cc2c(cc1Br)CC(C)NN=C2c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(OC)c(Br)cc2CC1C
Yield: 83.5 %

Procedure:
0.60 g (1.5 mmol) of 7-bromo-4-methyl-8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (Example 4, Step A) is dissolved in 12 ml of dry methylene chloride and mixed with 0.64 ml (10.5 mmol) of methyl isocyanate. After a reaction period of 9 days at 25° C., the solution is concentrated by evaporation, and the residue is recrystallized from ethanol (10 ml). 0.56 g (83%) of 7-bromo-4-methyl-3-methylcarbamoyl-8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine in the form of yellow crystals with a melting point of 224-226° C. is obtained.
Reaction SMILES: C(O)(C)C.[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]([N+:23]([O-])=O)=[C:15]([C:26]([F:29])([F:28])[F:27])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([C:26]([F:27])([F:28])[F:29])[C:16]([NH2:23])=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
Isopropanol (450 mL) was added to 4-benzyloxy-2,6-bis(trifluoromethyl)nitrobenzene (9.00 g, 24.6 mmol) and the latter was dissolved in the former by heating at 70° C. A solution of sodium dithionite (14.1 g, 81.2 mmol) in water (150 mL) was added dropwise to the resulting solution. After stirring for 30 minutes at the same temperature, a solution of sodium dithionite (7.28 g, 41.8 mmol) in water (150 mL) was added further. The reaction mixture was stirred at the same temperature for 14 hours and then, the isopropanol was distilled off under reduced pressure. Ethyl acetate was added to the resulting suspension to separate it into layers. The aqueous layer was extracted with ethyl acetate twice. The organic layers were combined, washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent, whereby 8.26 g (yield: 100%) of 4-benzyloxy-2,6-bis(trifluoromethyl)aniline was obtained as colorless needle-like crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O1CCOCC1>[C:12]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cnccc1N
Solvent: C1COCCO1
Product: COC(=O)c1cnccc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
A mixture of methyl 4-aminopyridine-3-carboxylate (100 g, 0.6 mol) and acetic anhydride (240 g, 2.4 mol) in anhydrous 1,4-dioxane (1.2 L) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and diluted with water (800 mL). The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate to pH 7. The formed solid was collected by filtration and dried in vacuo to afford 50 g of methyl 4-(acetylamino)pyridine-3-carboxylate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:33](Cl)([CH3:35])=[O:34]>C(Cl)Cl>[C:33]([O:25][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[CH:20][C:21]([F:24])=[CH:22][N:23]=2)[CH2:14][CH2:13]1)(=[O:34])[CH3:35]
Reactant: CC(=O)Cl
Reactant: OC(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A cold (5° C.) mixture of 1-(4-fluorophenyl)-4-(4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl)-1-butanol monohydrochloride1 (3.0 g, 7.8 mmol) and Et3N (2.38 mL, 17.1 mmol) in CH2Cl2 (55 mL) was treated dropwise (10 min) with AcCl (0.67 mL, 9.4 mmol). The reaction mixture was stirred at 5° C. for 0.25 h and then at 23° C. for 2 h before being diluted with CH2Cl2 (250 mL). The organic solution was washed with water (30 mL), saturated Na2CO3 solution to bring pH to 9, water (20 mL) and brine, dried (MgSO4) and concentrated in vacuo to a solid which was purified on silica gel column using a mixture of 30-40% AcOEt in CH2Cl2. The appropriate fractions were collected and concentrated in vacuo to a white solid, 2.93 g, 96%. Recrystallization from ether-hexane mixture afforded analytical sample, mp 76°-7° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH2:9]([OH:18])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16]O.[CH2:19]([O:21][P:22]([O:26]CC)[O:23][CH2:24][CH3:25])[CH3:20].[PH2](O)=O.[P]>>[CH2:19]([O:21][P:22]([CH:3]([CH2:2][C:1]([OH:8])=[O:7])[C:4]([OH:6])=[O:5])([O:23][CH2:24][CH3:25])=[O:26])[CH3:20].[CH2:1]([C:15]([O:14][CH:13]=[CH:12][O:11][CH2:10][CH2:9][OH:18])=[CH2:16])[CH3:2]
Reactant: OCCOCCOCCO
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CCOP(OCC)OCC
Agent: O=[PH2]O
Agent: [P]
Product: C=C(CC)OC=COCCO
Product: CCOP(=O)(OCC)C(CC(=O)O)C(=O)O

Procedure:
The procedure according to Example 1 was repeated using similar apparatus and under essentially similar conditions allowing for the differences in quantities of materials employed. In this example, for the materials of the previous Example 1, 4.0 mols of fumaric acid, 4.0 mols of triethyleneglycol, 4.0 mols of triethylphosphite and 0.5% of hypophosphorous acid were employed. The product of the reaction had an acid value of about 5, a hydroxyl value of about 34, triethylphosphite less than 0.1% and a phosphorus content of about 7.3%.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1>O1CCOCC1.ClCCl>[NH:12]1[CH2:13][CH2:14][CH:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[NH2:2])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
A solution of 4 M HCl in dioxane (25 mL) was added to tert-butyl 4-[3-(amino)phenyl]-1-piperidinecarboxylate (2.60 g, 9.00 mmol) in dichloromethane (250 mL). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, and the residue was dissolved in water (50 mL). The mixture was nuetralized using KOH pellets and extracted with methylene chloride (3×50 mL). The combined organic extracts were dried (MgSO4), concentrated and chromatographed to give the desired product (1.03 g). 1H NMR (400 MHz, CDCl3) δ 7.01 (t, 1H, J=7.6 Hz), 6.62-6.54 (m, 3H), 3.16 (br d, 2H, J=10.3 Hz), 2.75 (dt, 2H, J=2.7, 12.3 Hz), 2.56 (tt, 1H, J=3.6, 12.3 Hz), 1.81 (br d, 2H, J=12.3 Hz), 1.65 (dq, 2H, J=4.0, 12.3 Hz); ESMS m/e: 177.2 (M+H)+.