Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[OH-].[Na+].[CH2:5]([O:7][C:8]1[C:9]([N:41]2[CH2:46][CH2:45][CH:44]([C:47]([O:49]CC)=[O:48])[CH2:43][CH2:42]2)=[C:10]([F:40])[CH:11]=[C:12]2[C:17]=1[N:16]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:15]=[C:14]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][C:28]=1[CH3:38])=[O:24])[C:13]2=[O:39])[CH3:6].Cl>O.CN(C=O)C>[CH2:5]([O:7][C:8]1[C:9]([N:41]2[CH2:42][CH2:43][CH:44]([C:47]([OH:49])=[O:48])[CH2:45][CH2:46]2)=[C:10]([F:40])[CH:11]=[C:12]2[C:17]=1[N:16]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:15]=[C:14]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:29][C:28]=1[CH3:38])=[O:24])[C:13]2=[O:39])[CH3:6]
Reactant: CCOC(=O)C1CCN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(OC(F)(F)F)cc4C)cn(CC(F)(F)F)c3c2OCC)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1c(N2CCC(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
2 ml of methanol, 2.5 ml of DMF and 2 ml of a sodium hydroxide solution (2N) are added to 85 mg (0.126 mmol) of the compound of Example 78. The mixture is stirred for 1 h at room temperature, acidified with 1N-HCl to pH 1, diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution, dried over sodium sulfate and freed from the solvent on a rotary evaporator. The residue is dried under high vacuum. 81 mg of the title compound are obtained (96% of theory).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].C(N[C@H](C(O)=O)CCCCN)(O[CH2:11][CH:12]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=O.C([N:37](CC)CC)C.CO.C(Cl)Cl.CO>C(Cl)Cl>[NH2:37][CH:2]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[C:3]([OH:5])=[O:4]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCN(CC)CC
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCCCC(N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
830 mg (1.53 mmole) of the N-hydroxysuccinimide ester of 3β-(2'-carboxymethoxycholest-5-ene) obtained as previously described (Ahmad et al. J. Chem., 24, 143-151) was added to a solution of 746 mg (1.53 mmoles) of Nα-Fmoc-lysine trifluoroacetate (obtained by trifluoroacetic acid deprotection of Nα-Fmoc-NεBoc-lysine), and 0.214 ml of triethylamine in 5 ml of methylene chloride. The reaction mixture was stirred overnight at room temperature. After addition of methanol (5 ml), and methylene chloride (20 ml), the reaction mixture was washed with 10-2 aqueous HCl. The organic layer was dried, and evaporated to give crystals. Yield: 0.88 g (73%). m.p.=89° C. Rf=0.5 (methylene chloride/methanol, 9/1), m/z: 795 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([F:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[CH2:3][CH2:2]1.CI.[C:34](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:34][O:22][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:17][C:16]([F:30])=[CH:15][CH:14]=2)=[O:23]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Reaction time: 12 h
Yield: 60.5 %

Procedure:
2-(2,3-Dihydrobenzofuran-5-ylmethyl)-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (800 mg) was dissolved in DMF (8 ml), and methyl iodide (0.24 ml) and potassium carbonate (530 mg) were added at room temperature. The mixture was stirred for 12 hrs. Water was added to the reaction mixture, and crystals were collected by filtration and washed with water. After drying the crystals, recrystallization (ethyl acetate) gave the title compound (500 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:74][C:75]([CH3:79])([CH3:78])[CH2:76][NH2:77]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:30][CH2:31][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:77][CH2:76][C:75]([CH3:79])([CH3:78])[CH3:74])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: CC(C)(C)CN
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCC(C)(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2,2-dimethyl-1-propanamine (8.65 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (17.8 mg, 50%). LC-MS m/z 643 (M+H)+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.CC(O)=O.C(OCC)C>CO>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: N=C(NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)N[N+](=O)[O-]
Yield: 148 %

Procedure:
34.3 Grams (0.057 mole) of BOC-Phe-Arg(NO2)-CHA was dissolved in 171 ml (0.342 Mole) of 2N HCl/AcOH with a small amount of MeOH, and reacted at room temperature for 2 hours. After the reaction was completed, 2 liters of dried diethyl ether was added to the reaction mixture so as to precipitate crystals. The precipitated crystals were collected by filtration and dried to obtain 30.9 g (100%) of H-Phe-Arg(NO2)-CHA.HCl.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH3:8])[C:6]#N)[CH2:2][CH3:3].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.C([O:20]CC)C>>[CH2:1]([O:4][CH:5]([CH3:8])[C:6]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)=[O:20])[CH2:2][CH3:3]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCCOC(C)C#N
Reactant: CCOCC
Product: CCCOC(C)C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To 25 g (222 mmole) of 2-propoxypropionitrile (Example 96b) in 100 ml of diethyl ether was dropwise added 200 ml (200 mmole) of 1.0M 4-chlorophenylmagnesium bromide. After refluxing for 30 minutes the reaction mixture was cautiously quenched with 20 ml of water followed by a mixture of 25 ml of sulfuric acid and 75 ml of water. After stirring for 30 minutes the organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and distilled yielding 25.9 g of the title compound, bp 110°-125° C. at 0.3 torr.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6](N1CCN(C2C=CC(F)=CC=2)CC1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[Cl:40][C:41]1[CH:42]=[C:43]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:44]=[CH:45][C:46]=1[Cl:47]>O1CCCC1>[Cl:40][C:41]1[CH:42]=[C:43]([N:48]2[CH2:53][CH2:52][N:51]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:50][CH2:49]2)[CH:44]=[CH:45][C:46]=1[Cl:47]
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CN(C)CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 2.5 g (0.025 mole) of 1,1'-carbonyldiimidazole, 1.4 g (0.015 mole) of unsym-dimethylethylenediamine and 3.6 g (0.015 mole) of 1-(3,4-dichlorophenyl)piperazine in a total of 100 ml of tetrahydrofuran gave an oil which solidified when triturated with cyclohexane. White solid, the title compound, in the amount of 4.0 g (75%) was collected, m.p. 80°-83° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:36][CH2:37][CH2:38][C@H:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][OH:41])C1C=CC=CC=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:36][CH2:37][CH2:38][C@H:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][OH:41])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCNC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.082 g (0.22 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 0.059 g (0.29 mmol) of benzyl{(3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutyl}carbamate (Example 237A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.056 g (0.29 mmol) of EDC and 0.009 g (0.067 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.Cl[CH:26](Cl)C>CN(C)C=O>[C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH3:26])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Sc1ccccc1
Reactant: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1

Procedure:
A mixture of 2-phenylsulphenyl-4-trifluoromethylbenzoic acid (11.5 g), thionyl chloride (1 1.4 g), dimethylformamide (0.2 ml) and dichloroethane was heated at reflux for 90 minutes. The solution was then concentrated under reduced pressure and the residue was dissolved in methanol and heated at reflux for one hour. The resulting solution was poured into aqueous sodium bicarbonate and extracted with ether. The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated. The resulting material was crystallised from hexane to give methyl 2-phenylsulphenyl-4-trifluoromethylbenzoate (10.5 g) as white crystals, m.p. 58° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.ClC(OCCCC)=O.Br.[NH2:27][CH2:28][C:29]([N:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1([CH3:38])[CH3:37])=[O:30]>ClCCl>[CH3:37][C:32]1([CH3:38])[NH:33][C:34](=[O:36])[CH2:35][N:31]1[C:29](=[O:30])[CH2:28][NH:27][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C(O)CN1CCCC1=O
Reactant: CC1(C)NC(=O)CN1C(=O)CN
Agent: Br
Agent: CCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)CN1C(=O)CNC(=O)CN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An ice cold solution of 2-oxo-1-pyrrolidineacetic acid (1.03 g) and triethylamine (1.01 ml) in dichloromethane (20 ml) was treated dropwise with butyl chloroformate (0.92 ml). After stirring at 0° C. for 30 minutes a suspension of 1-(2-aminoacetyl)-2,2-dimethyl-4-imidazolidinone hydrobromide (1.82 g) and triethylamine (1.01 ml) in dichloromethane (20 ml) was added, and the temperature was gradually raised to room temperature. After stirring at room temperature for 1 day the suspension was evaporated under reduced pressure. The residue was chromatographed on a silica/gel column eluting with methanol/dichloromethane 1:1. The selected fractions were collected and evaporated, the residue was washed with ethyl acetate and crystallized from ethanol to give the title compound as a white solid, m.p. 229°-231° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[N:11]2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.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)C(C)C)(C)C>C(Cl)Cl>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:21]([C:17]2[S:16][C:15]([C:12]3[CH:13]=[CH:14][N:10]([CH2:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])=[CH:27][CH:26]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (0.1 g, 0.30 mmol) in methylene chloride (5 mL) was added 4-fluoro benzyl amine (0.04 g, 0.33 mmol), benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.146 g, 0.33 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.60 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (50 mL), washed with water (50 mL) and brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (hexanes:ethyl acetate, 1:1) to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (83 mg, 62% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 2H), 7.14 (d, J=4.0 Hz, 1H), 6.92-7.07 (m, 6H), 6.72 (d, J=4.0 Hz, 1H), 6.06 (bs, 1H), 4.58 (d, J=4.0 Hz, 2H), 4.34 (t, J=8.0 Hz, 2H), 3.16 (t, J=8.0 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=439.1; Rt=1.55 min; HRMS (M+H)+=439.14.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15](CC)[CH2:16][C:17]3C=CC(OC)=CC=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[NH:34][C@@H:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][C@H:36]1[OH:45].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[NH:34][C@@H:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][C@H:36]1[OH:45]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N[C@@H]3CCN(C(=O)OC)C[C@H]3O)c2Cl)nn2c(C#N)cnc12
Solvent: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCNc1nc(Nc2cc(C#N)cc(N[C@@H]3CCN(C(=O)OC)C[C@H]3O)c2Cl)nn2c(C#N)cnc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
To (3R,4R)-methyl 4-((2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)amino)-3-hydroxypiperidine-1-carboxylate (30.9 mg, 0.049 mmol) was added DCE (3 mL), anisole (5.35 μl, 0.049 mmol) and TFA (0.5 mL, 6.49 mmol); the reaction stirred 2 hr at 40° C. and solvents removed. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (3R,4R)-methyl 4-((2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)amino)-3-hydroxypiperidine-1-carboxylate (5.1 mg).
Reaction SMILES: C(=O)([O-])[O-:2].[Mg+2:5].[S:6](=[O:8])=[O:7]>>[S:6](=[O:2])([OH:8])[O-:7].[Mg+2:5].[S:6](=[O:2])([OH:8])[O-:7]
Reactant: O=C([O-])[O-]
Reactant: O=S=O
Agent: [Mg+2]
Product: O=S([O-])O

Procedure:
According to the invention a method of recovering magnesia from magnesium carbonate containing raw material includes the steps of forming a slurry of uncalcined raw material, heating the slurry to a temperature between 40° and 90° C., treating the slurry with sulphur dioxide to form soluble magnesium bisulphite, separating undissolved impurities from the solution of magnesium bisulphite, precipitating magnesium sulphite from the solution, separating the precipitate from the mother liquor and recovering magnesia from the separated precipitate.
Reaction SMILES: OCCN1C(=O)C=CC([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=N1.S(Cl)([Cl:28])=O>C(Cl)Cl>[ClH:28].[ClH:28].[C:20]1([C:12]2[CH:11]=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: c1ccc(-c2cc3ccccn3n2)cc1

Procedure:
A solution of 3-[2-(2-hydroxyethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.5 g) and thionyl chloride (0.13 ml) in methylene chloride (4 ml) was stirred at room temperature for 1 hour and evaporated in vacuo. To the residue was added dropwise a solution of 1-(2-hydroxyethyl)piperazine (0.78 g) in amyl alcohol (5 ml), and the suspension was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo, and the residue was purified by column chromatography on silica gel using chloroform as eluent. The obtained oil was treated with a 20% solution of hydrogen chloride in ethanol to afford 3-[2-{2-{4-(2-}ethyl}-3-oxo-2,3-hydroxyethyl)piperazin-1-yl}ethyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine dihydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[S:18]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:17](=[S:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1ccccc1C(=S)Cl
Solvent: ClCCl
Product: COc1ccc(CCNC(=S)c2ccccc2C)cc1OC

Procedure:
2-(3,4-Dimethoxyphenyl)ethylamine (4.8 ml), poly(4-vinylpyridine) (PVP) (5.7 g) and 2-methylthiobenzoyl chloride (5.3 g) were stirred in dichloromethane (50 ml) with cooling in a water bath at 20° for one night. The PVP was filtered off and washed with CHCl3. Evaporation of the extracts followed by flash chromatography (ethyl acetate/petroleum ether) gave the sub-title compound, mp 94°-95°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](O)=[O:25]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccco1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccco3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and furan-2-carboxylic acid following procedure I yielded the title compound after purification by preparative HPLC. MS (ISP): m/z=354.4 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH:12]3[CH2:13][CH2:14][CH:9]([CH2:10][CH2:11]3)[N:8]2C(OCC)=O)[CH:2]=1>[OH-].[Na+].C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH:12]3[CH2:13][CH2:14][CH:9]([CH2:10][CH2:11]3)[NH:8]2)[CH:2]=1
Reactant: CCOC(=O)N1C2CCC(CC2)C1c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cncc(C2NC3CCC2CC3)c1
Yield: 83 %

Procedure:
(+/-)-3-(3-pyridyl)-2-carboethoxy-2-azabicyclo[2.2.2]octane (XII) (500 mg, 1.92 mmol) was dissolved in a solution of 20% (w/v) NaOH in absolute ethanol (10 mL) and refluxed for 24 h. The organic solvent was evaporated on a rotary evaporator. The pH of the basic residue was adjusted to 9 by addition of a solution of 2N HCl in water and was extracted with ethyl acetate (4×10 mL). The organic extracts were dried over anhydrous K2CO3, and concentrated. The resulting oily residue was purified by distillation under reduced pressure (108°-110° C./0.4 mm Hg) to afford 300 mg (83%) of compound (XIII). 1H NMR (CDCl3): δ 8.62-8.61 (d, 1H), 8.44-8.41 (m, 1H), 7.80-7.72 (m, 1H), 7.24-7.21 (m, 1H), 4.30 (s, 1H), 3.71-3.63 (m, 1H), 2.20 (m, 1H), 2.0-1.51 (m, 8H), 1.42 (d, 1H).
Reaction SMILES: [CH2:1]([C:3]1[O:8]C(C)(C)[O:6][C:5](=O)[CH:4]=1)[CH3:2].[CH3:12][NH2:13].Cl>C1(C)C(C)=CC=CC=1>[CH3:12][NH:13][C:5](=[O:6])[CH2:4][C:3](=[O:8])[CH2:1][CH3:2]
Reactant: CCC1=CC(=O)OC(C)(C)O1
Reactant: CN
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCC(=O)CC(=O)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-ethyl-2,2-dimethyl-4H-1,3-dioxin-4-one (10.0 g, 64.0 mmol) in 20 ml of xylene was bubbled with methylamine gas at 110° C. for 3 hrs. After cooling to room temperature, 5.3 ml of 1N HCl aqueous solution was added and the mixture was stirred at r.t. for 2 hrs. The organic layer was separated, the water layer was extracted by Et2O (3×30 ml). The organic layers were combined and dried (Na2 SO4). After evaporation of solvent, N-methyl propionylacetamide was obtained as a colorless oil (4.25 g, 51%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[I-].[Na+].[C:8]([O:16][CH2:17][C@@H:18]1[O:23][C@@H:22]([O:24][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH2:26]Br)[CH2:21][CH2:20][CH2:19]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[C:8]([O:16][CH2:17][C@@H:18]1[O:23][C@@H:22]([O:24][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH2:26][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:21][CH2:20][CH2:19]1)(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OC[C@H]1CCC[C@H](OC(CBr)c2ccc(Cl)cc2Cl)O1)c1ccccc1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OC[C@H]1CCC[C@H](OC(Cn2ccnc2)c2ccc(Cl)cc2Cl)O1)c1ccccc1
Temperature: 130 °C
Reaction time: 6.5 h
Yield: 48.2 %

Procedure:
8.24 g of imidazole and 12.0 g of sodium iodide were added to a solution of 19.70 g of trans-6-benzoyloxymethyl-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran in 150 ml of dimethylformamide, and the resulting mixture was stirred on an oil bath at 130° C. for 6.5 hours. The reaction mixture was then cooled, poured into water and extracted with diethyl ether. The ethereal extract was washed with aqueous sodium chloride and dried over anhydrous sodium sulphate, after which the solvent was evaporated off. The residue was purified by column chromatography through silica gel eluted with a B 100:25:1 by volume mixture of ethyl acetate, benzene and triethylamine, to give 9.25 g of the title compound as a liquid.