Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[C:5]=1[N+]([O-])=O)([O-:3])=[O:2].[N+:23]([O-:26])([OH:25])=O>>[N+:23]([C:9]1[C:8]2[C:7](=[O:19])[C:6]3[C:15](=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14](=[O:18])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c1cccc2[N+](=O)[O-]
Yield: 1.8 %

Procedure:
5.00 kg of this dinitroanthraquinone mixture (consisting of 41.2% of 1,5-dinitroanthraquinone, 39.6% of 1,8-dinitroanthraquinone, 8.9% of 1,6-dinitroanthraquinone and 9.5% of 1,7-dinitroanthraquinone) together with 49.04 kg of 97 percent strength by weight nitric acid (molar ratio 45) continuously flow, per hour, onto the fourth tray of a 5-tray rectifying column at about 55° C. 29.65 kg/hour of 99 percent strength by weight nitric acid is taken off at the head of the column at a reflux ratio of reflux/take-off of 0.4. The column is operated under a head pressure of 200 mm Hg, a head temperature of about 50° C. being set up. 19.29 kg/hour of 70 percent strength by weight nitric acid are continuously added to the sump of the column at a temperature of about 70° C. The dinitro-anthraquinone mixture to be crystallised, in which the molar ratio of nitric acid to organic products is 30:1 and the nitric acid concentration is 82 percent by weight (weight ratio 7.7), is removed at the sump of the column at a temperature of about 70° C. 3.8 kg per hour of a dinitroanthraquinone mixture having a composition of 53.2% of 1,5-dinitroanthraquinone, 44.6% of 1,8-dinitroanthraquinone, 0.3% of 1,6-dinitroanthraquinone and 1.8% of 1,7-dinitroanthraquinone is isolated from the mixture thus obtained, by cooling to room temperature (25° to 30° C.), separating off by filtration the solid which has precipitated and then drying it.
Reaction SMILES: [C:1]([CH:5]1[C:10](CCCC)([OH:11])[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8][C:7]([C@H:20]2[N:24]([CH2:25][CH2:26][CH2:27][N:28]([CH3:41])[CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[C:23](=[O:42])[CH2:22][S:21]2)=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47]>C(O)C>[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47].[C:16]([C:9]1[CH:8]=[C:7]([C@H:20]2[N:24]([CH2:25][CH2:26][CH2:27][N:28]([CH3:41])[CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[C:23](=[O:42])[CH2:22][S:21]2)[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:10]=1[OH:11])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCCCC1(O)C(C(C)(C)C)=CC([C@@H]2SCC(=O)N2CCCN(C)CCOc2ccc3c(c2)OCO3)=CC1C(C)(C)C
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: CN(CCCN1C(=O)CS[C@H]1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Yield: 81.3 %

Procedure:
To a solution of (S)-(−)-2-(3,5-di-tert-butyl-4-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxy-phenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one (380 mg, 0.70 mmol) synthesized according to the process described in JP No. 6-206842/1994 in ethanol (10 ml) was added a solution of fumaric acid (65 mg, 0.56 mmol) in ethanol (10 ml) (prepared under preheating) and the mixture was stirred, then the solvent was removed under reduced pressure. The residue was combined with n-hexane and cooled in a freezer for 4 hours, then ether was added. The precipitate was filtered off and dried to give a white amorphous powder of the fumaric acid salt (300 mg). To a solution of this powder (52 mg) in acetone (1 ml) was added water (3 ml), and the mixture was heated under reflux for 10 minutes, then stirred at room temperature overnight. The resulting precipitate was filtered with suction, washed with water and dried to give white crystals (36.5 mg). mp: 109-117° C. Elementary analysis: calculated for C34H46N2O9.H2O: C, 60.34, H, 7.15, N, 4.14; found: C, 60.52, H, 6.84, N, 4.19.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.371 g, 0.602 mmol) prepared in Example 122b and triethylsilane (0.48 mL, 3.01 mmol) in dichloromethane (6.0 mL), trifluoroacetic acid (0.60 mL) was added at room temperature, and the reaction solution was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (ethyl acetate/methanol=6:1) to yield the title compound (0.28 g, 99%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:16](=[O:23])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH2:17].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:17][C:16](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:3][CH:4]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)#[N:15]
Reactant: CC(C)(C)OC(N)=O
Reactant: N#CC1(c2ccc(Br)cc2)CCNCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(C2(C#N)CCNCC2)cc1
Temperature: 115 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
The mixture of 4-(4-bromophenyl)piperidine-4-carbonitrile (347, 520 mg, 1.96 mmol), tert-butyl carbamate (460 mg, 3.92 mmol), Pd2(dba)3 (180 mg, 0.20 mmol), XantPhos (350 mg, 0.60 mmol), fine-powder Cs2CO3 (1.96 g, 6.0 mmol) in 30 mL dioxane was degassed using N2 stream for 5 min and stirred in 115° C. bath in N2 atmosphere for overnight. It was cooled to RT, diluted with EtOAc 200 mL and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 30% MeOH in DCM to afford tert-butyl 4-(4-cyanopiperidin-4-yl)phenylcarbamate (348, 230 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]#[N:23])[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:7]2.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1.C(Cl)Cl>[C:24]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:22]#[N:23])=[CH:3][C:2]=2[Cl:1])[CH2:7][CH:8]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1cc(Cl)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cc(Cl)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2C(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 28.1 %

Procedure:
To a solution of compound 163A (164 mg, 0.472 mmol) in pyridine (1 mL) and CH2Cl2 (1 my) at RT was added benzoyl chloride (82 μL, 0.71 mmol), and the mixture was then stirred at 50° C. for 16 h. After cooling to RT, the reaction was concentrated in vacuo and the resultant residue was taken into MeOH (4 mL), and Et3N (1 mL) added. The reaction was stirred at 70° C. for 1 h. After cooling to RT, the reaction was concentrated. The residue was diluted with 10% aqueous citric acid, then extracted with EtOAc (3×15 mL). The combined EtOAc extracts were concentrated. The resulting residue was purified using preparative HPLC (YMC S5 ODS 20×100 mm) eluting with MeOH (50-80%) in H2O for 8 min, and then 80% MeOH in H2O for 7 min to give the title compound (60 mg, 28%) as a white solid. HPLC: 99% at 6.2 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A 90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 452 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1)(=[O:11])=[O:10].FC(F)(F)C(O)=O>ClCCl>[N:19]1([C:14]2[C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:33])([F:32])[F:1])(=[O:11])=[O:10])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nccnc1N1CCNCC1)c1ccccc1C(F)(F)F
Reaction time: 2 h

Procedure:
tert-butyl 4-[3-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)pyrazin-2-yl]piperazine-1-carboxylate (1.46 g, 3 mmol) was dissolved in dichloromethane (50 mL) and trifluoroacetic acid (4.5 g, 40 mmol) was added at 0° C. The reaction mixture was stirred for 2 h. The solvents were evaporated and the residue redissolved in dichloromethane (50 ml) and evaporated to dryness to give the expected product N-(3-piperazin-1-ylpyrazin-2-yl)-2-(trifluoromethyl)benzenesulfonamide as a yellow solid (1.1 g, 95% yield, 95% purity by HPLC).
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3]/[CH:4]=[CH:5]/[Sn](CCCC)(CCCC)CCCC.C(OCC)C.C[Li].[Cu]C#N.[Si:34]([O:41][CH:42]1[CH2:46][C:45](=[O:47])[C:44]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]([O:56][CH3:57])=[O:55])=[CH:43]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].[Cl-].[NH4+]>O1CCCC1>[CH3:57][O:56][C:54](=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][C@@H:44]1[C@@H:43](/[CH:5]=[CH:4]/[CH2:3][C:2]([OH:1])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:42]([O:41][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH2:46][C:45]1=[O:47]
Reactant: COC(=O)CCCCCCC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Reactant: CCCCC(C)(O)C/C=C/[Sn](CCCC)(CCCC)CCCC
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC(C)(O)C/C=C/[C@H]1C(O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1CCCCCCC(=O)OC
Temperature: -40 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Into a dry flask was placed a solution of [(4RS, 1E)-4-hydroxy-4-methyl-1-octenyl]tri-n-butyltin (1.36 g, 3.15 mmol) in dry tetrahydrofuran (5 ml) under nitrogen atmosphere, and the mixture was cooled to 0° C. To this solution was dropped 5.7 ml (5.99 mmol) of a diethyl ether solution of methyllithium (1.05 mol/liter), and stirring was continued for 1 h, letting the temperature rise gradually to room temperature. After cooling to −40° C., copper (I) cyanide (141 mg, 1.58 mmol) was added and dissolved by letting the temperature rise gradually to 0° C. This reaction liquid was cooled to −78° C. and added with a solution of (±) methyl 7-(3-tert-butyldimethylsilyloxy-5-oxo-1-cyclopentenyl)heptanoate (318 mg, 0.9 mmol) in dry tetrahydrofuran (1.5 ml) was rapidly added. After stirring for 5 min, 20 ml of a saturated aqueous ammonium chloride/aqueous ammonia (9:1) was added, and stirring was continued for 30 min , letting the temperature rise gradually to room temperature. This mixture was extracted with ethyl acetate (80 ml) two times, and the combined organic layer was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to remove solvent. The residue was purified by silica gel column chromatography [ethyl acetate/hexane (1/5)] to give 413 mg (96% yield) of (±)-methyl(16RS, 13E)-11-tert-butyldimethylsilyloxy-16-hydroxy-16-methyl-9-oxoprost-13-en-1-oate as a colorless oil. The spectral data of IR and 1H NMR were identical with those of the example 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cn2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
To a solution of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate (17 g, crude) in THF/MeOH/water (300 mL) was added sodium hydroxide (4.3 g, 107.5 mmol), and the reaction was stirred at 70° C. for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to RT, acidified to pH≈5-6 with 1 M HCl and filtered. The solid was collected and dried to give the title compound (16 g, 96%) as a white solid, which was directly used in the next step without further purification. MS (ES+) C14H20N4O4 requires: 308. found: 253 [M−56+H]+.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]([O:39][CH3:40])[O:37][CH3:38])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]([O:37][CH3:38])[O:39][CH3:40])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(C(OC)OC)cc3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(C(OC)OC)cc3)cc2)cc1)C(=O)O
Yield: 99.8 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(4′-dimethoxymethylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (1.88 g), which is the product of Reference example 11, was reacted with aqueous sodium hydroxide solution (1N, 6.80 ml) and the reaction mixture was treated to give 2-butyl-3-[4-[2-(4′-dimethoxymethylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionic acid (1.78 g) as a pale brown solid.
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C>C(Cl)Cl>[NH2:9][C@H:10]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C[C@H](N)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 118.8 %

Procedure:
Hydrochloric acid (4.0M in 1,4 Dioxane) (4.18 mL, 16.73 mmol) was added in one portion to (S)-methyl 3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoate (Intermediate 19) (1.05 g, 3.35 mmol) in DCM (20 mL) at 20° C. The resulting solution was stirred at 20° C. for 5 hours. The reaction mixture was evaporated to give (S)-methyl 3-amino-3-(4-chlorophenyl)propanoate (hydrochloride) (0.850 g, 102%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ 2.98-3.04 (1H, m), 3.16-3.21 (1H, m), 3.58 (3H, s), 4.62-4.66 (1H, m), 7.50-7.52 (2H, m), 7.57-7.59 (2H, m), 8.66 (3H, s). m/z (ESI+) (M+H)+=214; HPLC tR=1.71 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:23])[N:21]=2)[CH:18]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)c1cn2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of 3 g of aniline in 366 mL of toluene cooled to 0° C. are added dropwise 22.5 mL of a 2M solution of trimethylaluminium in toluene, followed by addition, at 20° C., of 5.6 g of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate. The reaction mixture is stirred for 2 hours at room temperature. The resulting mixture is cooled to 4° C. and 150 mL of saturated ammonium chloride solution are then added. The reaction mixture is concentrated to dryness and is then taken up in 400 mL of water and 400 mL of dichloromethane. The organic phase is dried over magnesium sulfate, filtered through Celite and evaporated to dryness under reduced pressure to give 4.6 g of 6-bromo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of an off-white powder.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:15])[NH:5][C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:15])[N:5]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:4]=2[CH:3]=1
Reactant: BrCC1CO1
Reactant: Fc1ccc2c(c1)[nH]c1cccc(F)c12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c3c(F)cccc3n(CC3CO3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a stirred solution of 2,5-difluoro-9H-carbazole (0.530 g, 2.6 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.207 g, 3.1 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.432 mL, 5.2 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (0.59 g, 87%). 1H NMR (300 MHz, CDCl3) δ 8.13 (dd, 1H, J=8.7, 5.7 Hz), 7.38 (td, 1H, J=8.1, 5.4 Hz), 7.23 (d, 1H, J=8.4 Hz), 7.15 (dd, 1H, J=9.6, 2.1 Hz), 7.03 (ddd, 1H, J=9.6, 9.0, 2.4 Hz), 6.95 (ddd, 1H, J=9.9, 8.1, 0.6 Hz), 4.64 (dd, 1H, J=15.9, 3.0 Hz), 4.31 (dd, 1H, J=15.9, 5.1 Hz), 3.36 (m, 1H), 2.85 (t, 1H, J=4.5 Hz), 2.57 (dd, 1H, J=4.5, 2.4 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH:7]=[C:8]([P:12]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][O:13]1)[C:9]([CH3:11])=O)([O-:3])=[O:2].[NH2:22]/[C:23](/[CH3:29])=[CH:24]\[C:25]([O:27][CH3:28])=[O:26]>C(O)(C)C>[CH3:29][C:23]1[NH:22][C:9]([CH3:11])=[C:8]([P:12]2(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:7]([C:6]2[CH:19]=[CH:20][CH:21]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)P1(=O)OCCCO1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(P2(=O)OCCCO2)C1c1cccc([N+](=O)[O-])c1
Yield: 49.9 %

Procedure:
Into 80 ml of isopropanol were dissolved 5.5 grams of 2-(1-(3-nitrobenzylidene)-acetonyl)-2-oxo-1,3,2-dioxaphosphorinane and 2.1 grams of methyl 3-aminocrotonate and the mixture was heated to reflux for 10 hours. After the reaction, the reaction solution was concentrated in vacuo, the residue was made crystallized by addition of ethyl acetate, and crystals separated out were collected by filtration. The crude crystals were recrystallized from ethyl acetate to give 3.6 grams of methyl 2,6-dimethyl-4-(3-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate, m. p. 221°-3° C.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:9][CH3:10])[C@@H:5]([CH3:8])[CH2:6]O)[CH3:3]>S(Cl)(Cl)=O>[ClH:1].[CH2:2]([N:4]([CH2:9][CH3:10])[C@@H:5]([CH3:8])[CH2:6][Cl:1])[CH3:3]
Reactant: CCN(CC)[C@@H](C)CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCN(CC)[C@@H](C)CCl
Temperature: 60 °C
Yield: 164.3 %

Procedure:
(S)-2-Diethylaminopropanol hydrochloride (50 g) is added in small portions to thionyl chloride (110 cc) at 2° C. The solution obtained is then heated to 60° C. for 4 hours. Excess thionyl chloride is removed by distillation under reduced pressure (90 kPa) and ethyl ether (250 cc) is then added to the residue obtained. The resultant solid is filtered off, is rinsed with ethyl ether (300 cc) and is then recrystallized from methyl isobutyl ketone (150 cc). After filtration and washing with ethyl ether, (S)-2-diethylamino-1-chloropropane hydrochloride (45.6 g) is obtained in the form of white crystals melting at 103° C., [α]D20 =0 (c=0.7; ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2)=[O:7]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Nc1cccc2cnccc12
Product: COc1cc(C(=O)Nc2cccc3cnccc23)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxybenzoyl chloride was reacted with 5-aminoisoquinoline according to the procedure of Example 8 to produce 5-(3,4,5-trimethoxybenzamido) isoquinoline. This product was then reduced according to the procedure of Example 8 to yield 5-(3,4,5-trimethoxybenzamido)-1,2,3,4-tetrahydroisoquinoline HCl. After purification from methanol it had a melting point of 270°-271.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)=[CH:4][CH:3]=1.[C:21]([C:25]1[O:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CS(C)=O>[C:21]([C:25]1[O:29][N:28]=[C:27]([NH:30][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][C@@H:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10]3)=[CH:6][N:7]=2)[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Clc1ccc(CN2CCO[C@@H](c3ccccc3)C2)cn1
Reactant: CC(C)(C)c1cc(N)no1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(Nc2ccc(CN3CCO[C@@H](c4ccccc4)C3)cn2)no1
Temperature: 60 °C
Yield: 24 %

Procedure:
2.73 mL of (S)-4-(6-Chloro-pyridin-3-ylmethyl)-2-phenyl-morpholine in DMSO(0.1M solution) was added to 63 mg of 5-tert-Butyl-isoxazol-3-ylamine. 900 L of sodium bis(trimethylsilyl)amide (1M solution in tetrahydrofuran) was added and the reaction heated overnight at 60° C. on an orbital shaker. The reaction was filtered through a fritted cartridge. Purification was accomplished by preparatory liquid chromatography to give the title compound in 24% yield. EI m/z 393=MH+
Reaction SMILES: [C:1]([O:5]/[CH:6]=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:5][CH:6]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(/C=C\OC(C)(C)C)nc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(OC(C)(C)C)C1c1ccc(C)cn1
Reaction time: 8 h
Yield: 28.8 %

Procedure:
The solution of (Z)-2-(2-tert-butoxyvinyl)-5-methylpyridine (12-3) (1.20 g, 6.27 mmol) in toluene (20 mL) and anhydrous copper sulfate (100 mg, 0.63 mmol) was heated to 75° C. Then the solution of ethyl diazoacetate (2.17 g, 18.8 mmol) in toluene (10 mL) was added dropwise over 2 h. It was heated for another 2 h after the addition was completed. The mixture was restored to room temperature for overnight. The solvent was removed under reduced pressure and the residue was purified by silca gel chromatography with gradient eluent (PE/EA=40/1; 20/1; 10/1). The product was obtained as a yellow oil (500 mg, 34%). LRMS (ES) calculated M+H for C16H24NO3: 278.3. Found: 278.2.