Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>CO>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:14]([NH:15][N+:16]([O-:18])=[O:17])=[NH:19]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCCCc1ccccn1
Solvent: CO
Product: N=C(NCCCCc1ccccn1)N[N+](=O)[O-]

Procedure:
A solution of 2-(4-aminobutyl)pyridine (2.9 g) and S-methyl-N-nitroisothiourea (2.9 g) in methanol (50 ml) was heated at 50°-65° for 4-5 hours. Concentration, followed by recrystallisation of the residue yielded N-[4-(2-pyridyl)butyl]-N'-nitroguanidine.
Reaction SMILES: [CH2:1]([C:5]1([CH2:22][CH2:23][CH2:24][CH3:25])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7](C(OCC)=O)[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]>O1CCOCC1.Cl>[CH2:1]([C:5]1([CH2:22][CH2:23][CH2:24][CH3:25])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[CH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CCCCC1(CCCC)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A solution of the product of Example 4F (200 mg, 0.58 mmol) in dioxane (3 mL) and 10% HCl solution (10 mL) was stirred at 100° C. for 5 hours, cooled to 25° C. and extracted with dichloromethane (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was recrystallized from hexanes to give the title compound (140 mg, 88%). 1H NMR (300 MHz, DMSO-d6): δ 11.72, 11.46 (s, 1 H), 7.92 (m, 1 H), 7.61 (m, 1 H), 7.37 (m, 2 H), 5.81, 5.64 (two s, 1 H), 1.99 (m, 4 H), 1.05 (m, 4 H), 0.82 (m, 2 H), 0.67 (t, J=6.99 Hz, 6 H), 0.44 (m, 2 H).
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[C:9]([CH:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][OH:26])[C:15]=2[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH2:1]([N:8]([CH3:27])[C:9]([CH:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])[C:15]=2[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccccc1)C(=O)C1CCCc2c1c1ccccc1n2CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)C1CCCc2c1c1ccccc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 31.8 %

Procedure:
To a solution of 9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid benzyl-methyl-amide (28) (36 mg, 0.1 mmol) in dichloromethane (2 mL) was added pyridine (7.91 g, 1.0 mmol, 8.1 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (57 mg, 0.5 mmol, 0.04 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×10 mL) and water (2×10 mL), dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (20-80% B, 4 g, 45 CV, 18 mL/min) to afford 14 mg (32%) of methanesulfonic acid 2-[4-(benzyl-methyl-carbamoyl)-1,2,3,4-tetrahydro-carbazol-9-yl]-ethyl ester as a yellow oil. The structure was confirmed by 1H NMR (CDCl3) δH 1.10-2.40 (5H, m), 2.51 (1.5H, s, OSO2CH3), 2.54 (1.5H, s, OSO2CH3), 2.70-2.90 (2H, m), 3.08 (1.5H, s, NCH3), 3.15 (1.5H, s, NCH3), 3.40-3.70 (1H, m), 4.10-4.80 (4H, m), 7.00-7.50 (9H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:27]([N:30]([CH2:34][CH:35]1[CH:40]([NH2:41])[CH:39]2[CH2:42][CH2:43][N:36]1[CH2:37][CH2:38]2)[CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:41][CH:40]1[CH:39]2[CH2:42][CH2:43][N:36]([CH2:37][CH2:38]2)[CH:35]1[CH2:34][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])=[O:9]
Reactant: CCCN(CCC)CC1C(N)C2CCN1CC2
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)CC1C(NC(=O)c2cc(Cl)c(NC)cc2OC)C2CCN1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A solution of 5-chloro-2-methoxy-4-(methylamino)benzoic acid (3.35 g, 15.5 mmoles) in anhydrous tetrahydrofuran (20 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (2.56 g, 15.8 mmoles), and stirred for one hour at room temperature. Nitrogen was bubbled through the solution for 20 minutes, and a solution of 2-(di-n-propylaminomethyl)-1-azabicyclo[2.2.2]-octan-3-amine (3.95 g, 15.8 mmoles) in tetrahydrofuran (10 ml) was added dropwise. The mixture was maintained at room temperature for 18 hours, and at 50° C. for 1 hour, then concentrated in vacuo. The residue was partitioned between methylene chloride and 1.0N aqueous sodium carbonate, and the organic layer was separated. The aqueous solution was extracted with methylene chloride, and the combined organic solution was dried (Na2SO4) and concentrated in vacuo. The residue was filtered through alumina (eluted with 3% methanol/methylene chloride) to provide 5.38 g (79%) of a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[F:11].[Cl-].[NH4+:13]>CO.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:13])=[CH:4][C:3]=1[F:11]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Agent: [Fe]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Nc1ccc(F)c(F)c1
Temperature: 60 °C
Yield: 43 %

Procedure:
Iron powder (28.1 g, 0.502 mol) was added as small portions to 1,2-difluoro nitrobenzene (20.0 g, 0.126 mol) in methanol (200 ml) and heated to 60° C. Ammonium chloride (48.4 g, 0.91 mol) in water (100 ml) was added drop wise and the reaction mixture refluxed for 5 hr. The reaction mixture was filtered over Celite and washed with methanol. Methanol was removed, and the aqueous layer was extracted with ethylacetate, washed with brine, dried over sodium sulphate and concentrated to yield 1,2-difluoro-4-aminobenzene (7 g, 43%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][CH:59]=[CH2:60])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH:61][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][CH:59]=[CH2:60])=[N:56][C:52]=2[CH:51]=1
Reactant: C=CC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)but-3-enylamine in tetrahydrofuran. Yield: %; Rf value: 0.34 (silica gel: dichloromethane/ethanol=9:1); C24H25ClN4O2 (436.95); mass spectrum: (M+H)+=437/439 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:34][CH2:35][O:36][CH2:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:33]4[CH2:38][CH2:37][O:36][CH2:35][CH:34]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(C3=CCOCC3)c2n1C
Temperature: 140 °C
Yield: 15.6 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (122 mg, 0.31 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (85 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium (36 mg, 10 mol %) and caesium carbonate (204 mg, 0.63 mol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon gas then heated at 140° C., for 30 min, by microwave irradiation. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-75%, 0.1% NH4OH in acetonitrile/water) to afford 432 as a white solid (19 mg, 15%). LCMS (Method K): RT 2.79 min [M+H]+ 394.16. 1H NMR (DMSO-d6, 400 MHz): δ 8.07 (1H, s), 7.69 (1H, m), 7.55 (1H, dd, J=8.76, 4.82 Hz), 7.30 (2H, br s), 7.04 (1H, dd, J=10.42, 8.75 Hz), 5.87 (1H br s), 5.70 (1H, m), 4.24 (2H, s), 3.86 (2H, m), 3.73 (3H, s), 2.45-2.23 (2H, m), 1.58 (3H, d, J=6.72 Hz)
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([F:15])[CH2:12][N:11](CC2C=CC(OC)=CC=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([F:15])[CH2:12][NH:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2C[C@H](F)C[C@@H](O[Si](C)(C)C(C)(C)C)C2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](F)C1
Reaction time: 8 h

Procedure:
To a solution of (3R,5R)-3-(tert-butyldimethylsilyloxy)-5-fluoro-1-(4-methoxybenzyl)piperidine (1 eq) in 5 mL of methanol was added 10% Pd/C (0.2 eq). The resulting suspension was stirred at H2 atmosphere overnight. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel, washed with MeOH, then concentrated in vacuo to yield (3R,5R)-3-(tert-butyldimethylsilyloxy)-5-fluoropiperidine, which was used to next step without further purification. LC/MS (m/z): 234.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:32][C:33](=[O:34])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C=NC1CCCCC1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)NC4CCCCC4)cc3)cc2C1=O

Procedure:
The compound of example 33 was prepared analogous to compound of example 7 by reaction of compound of example 6 with cyclohexyl isocyanate. The compound of example 33 was used directly without isolation for the preparation of compound of example 34.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1>>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:25]1[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=2)[CH2:27][CH2:26]1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(CN2CCC(N(C)C(=O)COc3nc(C)c(NC(=O)OC(C)(C)C)c(C)n3)CC2)c1

Procedure:
The title compound was synthesized from Compound 31 and 1-(bromomethyl)-3-methoxybenzene in the same manner as in Example 32.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH2:27][CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([F:29])[CH:9]=3)[C:4]=2[CH:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ClCCl.[OH-].[Na+]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:29])[CH:9]=2)[C:4]2[CH:3]=[C:2]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:15]=[CH:14][C:13]=2[N:12]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:17])=[O:18])[CH3:28]
Reactant: OB(O)c1ccccc1
Reactant: CCC1c2cc(F)ccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC1c2cc(F)ccc2-c2cc(-c3ccccc3)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
A stirred solution of 2-bromo-6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (Example 44, Step c, 0.25 g, 0.52 mmol) and phenylboronic acid (0.06 g, 0.52 mmol) in tetrahydrofuran (5 mL) was treated under nitrogen with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (0.01 g, 0.02 mmol) and a 5 N aqueous sodium hydroxide solution (0.2 mL, 1 mmol). The reaction mixture was heated at reflux for twelve hours, cooled to room temperature, and quenched with a saturated, aqueous, sodium chloride solution (10 mL) and diethyl ether (50 mL). The separated organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a crude product. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4) to yield the title compound as a solid (0.13 g, 50%);
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][Cl:19])=[CH:11][CH:10]=1)=O)C.O.[NH2:22][NH2:23]>C(O)(C)C>[Cl:19][CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH2:6][CH2:5][C:4](=[O:3])[NH:22][N:23]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(OCCCCl)cc1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: O=C1CCC(c2ccc(OCCCCl)cc2)=NN1

Procedure:
In a 500 mL round bottom flask, 4-[4-(3-chloro-propoxy)-phenyl]-4-oxo-butyric acid ethyl ester (7.85 g, 26.3 mmol), and hydrazine monohydrate (2.55 mL, 52.7 mmol), in isopropanol (200 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 5.2 g (74%). MS m/z 267 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[C:5]2[NH:6][CH:7]([C:14]3[C:15]([CH3:20])=[N:16][N:17]([CH3:19])[CH:18]=3)[CH2:8][CH:9]([C:10]([F:13])([F:12])[F:11])[N:4]2[N:3]=1>CO>[Br:1][C:2]1[CH:21]=[C:5]2[NH:6][C@@H:7]([C:14]3[C:15]([CH3:20])=[N:16][N:17]([CH3:19])[CH:18]=3)[CH2:8][C@@H:9]([C:10]([F:11])([F:12])[F:13])[N:4]2[N:3]=1
Reactant: Cc1nn(C)cc1C1CC(C(F)(F)F)n2nc(Br)cc2N1
Solvent: CO
Product: Cc1nn(C)cc1[C@H]1C[C@@H](C(F)(F)F)n2nc(Br)cc2N1

Procedure:
The racemic 2-bromo-5-(1,3-dimethyl-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1.5 g, 4.1 mmol, Preparation 8) was dissolved in methanol (35 mL) and the cloudy solution was gently warmed providing a clear solution. The solution was then filtered through a medium porosity Buchner funnel. The clear filtrate was directly used for chiral HPLC purification. 1 mL of this solution was loaded onto a 2.1 cm×25 cm Chiralcel OD column and eluted with a mobile phase comprising of isopropyl alcohol and methanol (1:1 ratio) at a flow rate of 15 mL/min. The two (R and S) enantiomers were collected separately. 27 such injections were carried out and the pooled fractions of pure (R and S) enantiomers were concentrated under reduced pressure. The title compound was isolated as a white powder (0.71 g, 1.95 mmols, >95% ee).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][C:4]=2[N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:38]([O:40][C:41](=[O:77])[CH2:42][CH2:43][CH2:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][C:59]2[CH:64]=[C:63]([S:65]([CH3:68])(=[O:67])=[O:66])[CH:62]=[C:61](I)[CH:60]=2)[C:47]=1[CH2:70][CH2:71][C:72]([O:74][CH2:75][CH3:76])=[O:73])[CH3:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[CH2:38]([O:40][C:41](=[O:77])[CH2:42][CH2:43][CH2:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][C:59]2[CH:64]=[C:63]([S:65]([CH3:68])(=[O:67])=[O:66])[CH:62]=[C:61]([C:8]3[CH:7]=[CH:6][C:5]4[S:1][CH:2]=[N:3][C:4]=4[CH:9]=3)[CH:60]=2)[C:47]=1[CH2:70][CH2:71][C:72]([O:74][CH2:75][CH3:76])=[O:73])[CH3:39]
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4scnc4c3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 100 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a mixture of benzothiazole-5-ylboronic acid pinacol ester (151.5 mg, 0.58 mmol), palladium acetate(II) (6.6 mg, 0.029 mmol), and triphenylphosphine (15.4 mg, 0.058 mmol) in dioxane (5 mL) were added 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (200 mg, 0.29 mmol), potassium phosphate (126.9 mg, 0.58 mmol), and water (10 mg) at room temperature under nitrogen atmosphere. Then, the brown reaction mixture was heated to 100° C. and stirred for 2 h at which time the TLC of the reaction mixture indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and diluted with water (50 mL) and ethyl acetate (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic extracts were washed with water (100 mL) and brine solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent under reduced pressure gave the colored residue which was purified by using an ISCO 40 g column, eluting with 2-25% ethyl acetate in hexanes to afford 4-[3-[6-(3-benzothiazol-5-yl-5-methanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (110 mg, 54.4%) as a light brown solid: ES(+)-HRMS m/e calcd for C37H45NO8S2 (M+H)+ 696.2660, found 696.2658.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[CH:17][C:18]([CH:20]=[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31])=O.[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].C([NH+]1C2=NC3C(N=C2N(CC)C1C#CC=C1N(CC)C2=NC4C(N=C2N1CC)=CC=CC=4)=CC=CC=3)C>N1C=CC=CC=1>[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].[CH3:6][N+:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17]#[C:18][CH:20]=[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31]
Reactant: CN1C(=CC(=O)C=C2C=Cc3ccccc3N2C)C=Cc2ccccc21
Agent: CCN1C(=CC#CC2N(CC)c3nc4ccccc4nc3[NH+]2CC)N(CC)c2nc3ccccc3nc21
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CN1C(=CC#Cc2ccc3ccccc3[n+]2C)C=Cc2ccccc21
Reaction time: 0.08 h
Yield: 35 %

Procedure:
Phosphoryl chloride (1.0 ml) is added to a stirred suspension of 1,3-Bis(1-methyl-2-(1H)-quinolylidene)acetone (0.68 g, 0.002 mol) in pyridine (10 ml). The mixture is stirred for 5 min., then the solid is collected and washed with a little pyridine, then with ether. The dye is converted to its perchlorate salt by solution in methanol, followed by addition of aqueous sodium perchlorate solution. After recrystallization from acetonitrile, the yield of purified dye is 0.30 g (36%) with the melting point indistinct. The following two dyes were prepared by procedures similar to that described above: 1,3-Diethyl-2-[(1,3-diethyl-1H-imidazo[4,5-b]quinoxalin-2-(3H)-ylidene)-1-propynyl]-1H-imidazo[4,5-b]quinoxalinium perchlorate. ##STR20## Recrystallized from acetonitrile. Purified yield 35% mp >300°. 1,3,3-Trimethyl-2-[(1,3,3-trimethyl-2-indolinylidene)-1-propynyl]-3H-indolium perchlorate. ##STR21## Recrystallized from methanol. Purified yield 43% mp. 194°-7° dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:10]2[CH3:19])=[C:4]([N+:20]([O-])=O)[CH:3]=1.O1CCCC1.[H][H]>[Ni].CO>[NH2:20][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:10]1[CH3:19]
Reactant: [H][H]
Reactant: COC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])C(C)C1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N1CCC(Nc2ccc(Cl)cc2N)C(C)C1

Procedure:
A mixture of 51 parts of methyl 4-(4-chloro-2nitrophenylamino)-3-methyl-1-piperidinecarboxylate, 270 parts of tetrahydrofuran and 96 parts of methanol is hydrogenated at normal pressure and at normal temperature with 15 parts of raney-nickel catalyst. After the calculated amount of hydrogen is taken up (6 hours), the catalyst is filtered off and the filtrate is evaporated. The oily residue is triturated in warm 2,2'-oxybispropane. After cooling, the product is filtered off, pulverized in a mortar and triturated again in 2,2'-oxybispropane. The product is filtered off and dried, yielding methyl 4-(2-amino-4-chlorophenylamino)-3-methyl-1-piperidinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:12])[N:3]=1.Cl[CH2:14][CH:15]([OH:36])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:14][CH:15]([OH:36])[CH2:16][N:17]2[CH2:18][CH2:19][N:20]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)[N:3]=1
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Oc1cccc2nc(Cl)ccc12
Product: OC(COc1cccc2nc(Cl)ccc12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 51.2 %

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 1 g of 2-chloro-5-hydroxyquinoline and 2.88 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine synthesized in Example 23-(b), in order to obtain 1.39 g of 2-chloro-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][C:12]=1[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[CH3:20][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:11]=1[N:10]1[CH:3]=[CH:7][CH:6]=[CH:5]1)[C:15]([NH2:17])=[O:16]
Reactant: Cc1cc(C(N)=O)ccc1N
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(N)=O)ccc1-n1cccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 671.6 %

Procedure:
The 2,5-dimethoxy-tetrahydrofuran (106 g, 80 mmol) was added to the solution of 4-amino-3-methylbenzamide (100 g, 66.7 mmol) in AcOH (300 mL). The mixture was stirred at 80° C. for about 1.5 h and then cooled to room temperature. The solution of Na2CO3 was added dropwise at 0° C. and extracted with ethyl acetate for three times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and washed with petroleum ether. The resultant solid was filtrated and dried to afford 3-methyl-4-(1H-pyrrol-1-yl)benzamide as a pale solid (89.7 g, yield 67%).