Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl-].[NH4+].C[N:24](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[C:10]([C:12]([NH2:24])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc2nc(Cl)nc(N3CCOCC3)c2n1

Procedure:
2-Chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carboxylic acid from Example 118 (0.12 g) was reacted with ammonium chloride (7 eq), HATU (1.5 eq) and DIPEA (4 eq) in DMF (5.2 mL) for 30 minutes. The reaction mixture was then diluted with water and the orange solid was collected by filtration to give 90 mg of 2-chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carboxamide.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:20]([CH2:29][OH:30])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@H:20]([CH:29]=[O:30])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
Oxalyl chloride (3.3 mL, 2M in CH2Cl2, 6.42 mmol) was stirred in dichloromethane (3 mL) in a three-necked flask. The reaction mixture was cooled to −78° C., and dimethyl sulfoxide (0.91 mL, 12.85 mmol) was added so that the internal temperature did not exceed −65° C. The reaction mixture was then stirred for 15 minutes. The (3R,4S)-3-hydroxymethyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (713 mg, 2.57 mmol) in dichloromethane (6 mL) was added dropwise keeping the internal temperature below −65° C. and then stirred for 15 minutes. Diisopropylethylamine (4.5 mL, 25.7 mmol) was added keeping the internal temperature below −65° C. and then stirred for 20 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give a colorless oil, which was purified by flash silica gel chromatography eluting with ethyl acetate: hexanes (1:4) to give 496 mg (70%) of (3R,4S)-3-formyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[N:40][CH:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[N:40][CH:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J24) (1.0 mg, 3.05 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K24) (1.22 g, 3.05 mmol) according to the general procedure M. Obtained as a light brown foam (620 mg, 31%).
Reaction SMILES: Br[C:2]1[C:3]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[CH2:33]([Sn](CCCC)(CCCC)C#CC)[CH2:34][CH2:35]C>CCOC(C)=O>[C:33]([C:2]1[C:3]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)#[C:34][CH3:35]
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC#Cc1cccnc1[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1

Procedure:
To a microwave vial containing (S)-tert-butyl ((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate (500 mg, 1.159 mmol) and a stir bar was added 1,4-dioxane (6 mL). To this solution was added tetrakis(triphenyl-phosphine)palladium(0) (67.0 mg, 0.058 mmol, 0.05 eq) and tributyl(prop-1-yn-1-yl)stannane (458 mg, 1.391 mmol, 1.2 eq). The vial was capped and irradiated in a microwave at 120° C. for 20 min. The vial was allowed to cool, diluted with hexanes (5 mL) and loaded directly to a normal phase silica gel column (80 g ISCO, 0 to 40% EtOAc in hexanes) to provide (S)-tert-butyl ((3-(prop-1-yn-1-yl)-pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[CH2:40][CH2:41][CH2:42][OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55].O>C(Cl)Cl>[CH3:53][S:54]([O:43][CH2:42][CH2:41][CH2:40][C@H:10]1[O:11][C@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:56])=[O:55]
Reactant: OCCC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)propanol (3.35 g, 5.75 mmol) in CH2Cl2 (30 mL) at 0° C. was added DIPEA (1.25 mL, 7.19 mmol) and followed by dropwise addition of methanesulfonyl chloride (538μL, 6.9 mmol). After stirring at 0° C. for 1 hr, the reaction mixture was poured into water (50 mL). The organic layer was separated and washed with sat'd NaHCO3 (50 mL), brine (30 mL), dried over MgSO4, filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.76-1.90 (m, 3H), 1.90-1.99 (m, 2H), 3.00 (s, 3H), 3.58-3.66 (m, 2H), 3.68-3.74 (m, 2H), 3.77-3.85 (m, 2H), 4.06 (m, 1H), 4.52 (d, J=10.7, 1H), 4.54 (d, J=12.1, 1H), 4.65 (d, J=12.1, 1H), 4.66 (d, J=11.6, 1H), 4.76 (d, J=11.6, 1H), 4.85 (d, J=10.9, 1H), 4.98 (d, J=10.9, 1H), 7.18 (m, 2H), 7.30-7.40 (m, 18H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23]>>[F:21][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:22]#[N:23])[CH:29]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: N#Cc1cccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-Cyanobenzene boronic acid. MS (M+H) 378.2
Reaction SMILES: [CH:1]1[C:6]2[CH:7]([CH2:10][C:11]#[N:12])[CH2:8][CH2:9][C:5]=2[CH:4]=[CH:3][N:2]=1.[NH2:13]OC1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[C:28]#[CH:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:11]([CH2:10][CH:7]1[C:6]2[C:1]3[N:2]([N:13]=[CH:29][C:28]=3[C:27]([O:31][CH2:32][CH3:33])=[O:30])[CH:3]=[CH:4][C:5]=2[CH2:9][CH2:8]1)#[N:12]
Reactant: C#CC(=O)OCC
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: N#CCC1CCc2ccncc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnn2ccc3c(c12)C(CC#N)CC3
Temperature: 40 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
To a solution of 6,7-dihydro-5H-cyclopenta[c]pyridin-7-ylacetonitrile (1.77 g, 11.2 mmol) in acetonitrile (22 mL) was added 1-(aminooxy)-2,4-dinitrobenzene (5.00 g, 25.1 mmol), and the mixture was stirred at 40° C. for 16 hr. The solvent was evaporated under reduced pressure. Half of the residue was dissolved in dimethylformamide (22 mL), ethyl propiolate (681 μL, 6.72 mmol) and potassium carbonate (1.55 g, 11.2 mmol) were added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was diluted with water, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→50/50) to give the title compound (440 mg).
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].Cl.[Cl:6][C:7]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:34][C:33]3[CH:32]=[N:31][N:30]([CH3:35])[C:29]=3[NH:28][C:27]3[CH:36]=[CH:37][CH:38]=[CH:39][C:26]2=3)=[O:24])[CH:20]=[CH:19][C:8]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCN(C(C)C)C(C)C.CN(C=O)C>[Cl:6][C:7]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:34][C:33]3[CH:32]=[N:31][N:30]([CH3:35])[C:29]=3[NH:28][C:27]3[CH:36]=[CH:37][CH:38]=[CH:39][C:26]2=3)=[O:24])[CH:20]=[CH:19][C:8]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:14][CH2:15][N:16]([CH2:1][CH2:2][CH3:3])[CH2:17][CH2:18]1)=[O:12]
Reactant: CCC=O
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CNC(=O)C3CCNCC3)c(Cl)c1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN1CCC(C(=O)NCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of propionaldehyde (0.29 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of piperidine-4-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide hydrochloride (Compound number 1109) (2.8 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=521.4
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25](Cl)(=O)[CH2:26][CH3:27].[OH2:30]>C1COCC1>[CH:26]1([CH2:2][CH2:3][C:1]([NH:4][CH:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10]2)=[O:30])[CH2:27][CH2:25]1
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCC2CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
0.8 g (3.3 mmol) of tert-butyl 4-cyclopropylaminopiperidine-1-carboxylate, 0.48 mL (3.3 mmol) of triethylamine and 0.56 mL (3.3 mmol) of propionyl chloride are dissolved in 50 mL of THF. The reaction medium is stirred for 2 hours at room temperature. The reaction is stopped by adding water and the organic products are then extracted with dichloromethane. The organic phase is dried and then evaporated. The crude product obtained is chromatographed on silica gel (eluent: 6/4 heptane/ethyl acetate). 0.87 g of tert-butyl 4-(cyclopropylpropionylamino)piperidine-1-carboxylate in the form of a colourless oil is obtained in a yield of 89%.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16](O)=[O:17])[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:11]1[C:12]2[C:13]3([C:16]([N:27]4[CH2:28][CH2:29][CH:24]([OH:23])[CH2:25][CH2:26]4)=[O:17])[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: OC1CCNCC1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccccc12
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(N1CCC(O)CC1)C12CC(c3ccccc31)c1ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (24.1 mmol) in toluene (70 mL) was added thionyl chloride (2.28 mL, 31.3 mmol, 1.3 eq). The reaction was heated to reflux monitoring gas evolution with a mineral oil bubbler. The system reached a steady state within 40 min at which time it was slightly cooled and 4-hydroxypiperidine (6.08 g, 60.3 mmol, 2.5 eq) was added portionwise. A significant amount of heat is evolved and the reaction became dark. The suspension was heated to reflux for 2 h, cooled to room temperature and stirred for 18 h. The reaction was diluted with ethyl acetate (200 mL) and washed with 3N HCl (2×100 mL), 2.5N NaOH (2×100 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The procedure yielded the title compound in quantitative yield as a viscous oil. TLC analysis (Rf 0.54, 10% methanol in CHCl3). MS (Cl, CH4) m/z 320 (M+1, 100), 348 (M+29,22), 302 (16)
Reaction SMILES: [CH2:1]([Li])CCC.[I-].[CH2:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH2:19][CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][OH:9].[CH2:40]([O:42][C:43]([C:45]1(C=O)[CH2:49][CH:48]=[CH:47][N:46]1[CH3:50])=[O:44])[CH3:41]>O1CCCC1>[CH2:40]([O:42][C:43]([C:45]1[N:46]([CH3:50])[CH:47]=[C:48]([CH:1]=[CH:20][CH2:19][C:12]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:7][CH2:8][OH:9])[CH:49]=1)=[O:44])[CH3:41]
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1(C=O)CC=CN1C
Reactant: COc1ccc(OCCO)c(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C=CCc2cc(OC)ccc2OCCO)cn1C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A solution of 1.6M n-butyllithium (4.0 ml, 6.0 mmol) was added to a suspension of 3.45 g (5.90 mmol) of 2-[2-(3-oxapropyloxy)-5-methoxyphenyl]ethyltriphenylphosphonium iodide in 20 ml of dry tetrahydrofuran at 0°. After 30 minutes a solution of 1.10 g (6.07 mmol) of 2-ethoxycarbonyl-1-methylpyrrole-2-carboxaldehyde in 5 ml of dry tetrahydrofuran was added and the solution was stirred for 30 minutes. The mixture was partitioned between ether and water and the ether layer was washed with water, dried (Na2SO4) and evaporated. The residue was chromatographed on silica using 20% ethylacetatehexane to afford 1.78 g (85%) of 2-ethoxycarbonyl-1-methyl-4-[2-(3-oxapropyloxy)-5-methoxyphenyl]propenylpyrrole as a colorless glass.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([NH:46][C:47](OC2C=CC=CC=2)=[O:48])[C:33](=[CH:44][CH:45]=1)[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:47]([NH:46][C:32]2[CH:31]=[C:30]([Cl:29])[CH:45]=[CH:44][C:33]=2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[O:48])(=[O:19])=[O:20])=[CH:14][C:13]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(S(N)(=O)=O)ccc1NC(=O)OCc1ccccc1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)ccc1NC(=O)OCc1ccccc1
Yield: 82.9 %

Procedure:
834 mg (2.05 mmol) of 4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonamide and 783 mg (2.05 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 17 to obtain 1.18 g (yield 83%) of benzyl 2-{[(4-benzyloxycarbonylamino-3-t butoxycarbonylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, CDCl3): 1.56 (9H, s), 5.22 (2H, s), 5.37 (2H, s), 7.04 (1H, dd), 7.33-7.42 (10H, m), 7.97 (1H, d), 8.14 (1H, d), 8.45 (1H, d), 8.60 (1H, d), 8.65 (1H, d), 11.01 (1H, s), 11.11 (1H, s).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC1C(O)=C(Cl)C(Cl)=C(Cl)C=1Cl.C([N+]#[C-])(C)C.Cl.[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH2:46])[CH3:42]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH:46][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:42]
Reactant: CCOC(=O)CN
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [C-]#[N+]C(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 82 %

Procedure:
A solution of 6.0 (20 mM) N-carbobenzoxy-L-phenylalanine, 5.3 g (20 mM) pentachlorophenol, and 2.0 g (30 mM) is isopropyl isonitrile in 40 ml chloroform was mixed with a solution of 2.8 g (20 mM) glycine ethyl ester hydrochloride and 2.02 g (20 mM) triethylamine in 30 ml chloroform. The mixture was heated at 50°C for 24 hours and evaporated. The residue was taken up in 150 ml ethyl acetate. The solution was washed sequentially with 100 ml water, 120 ml 1-N hydrochloric acid, four times 120 ml 5% sodium bicarbonate solution, and again with 100 ml water, then dried with desiccated sodium sulfate and evaporated. When the residue was crystallized from ethyl acetate and petroleum ether, 6.3 g N-carbobenzoxy-L-phenylalanyl-glycine ethyl ester was obtained (82 percent yield). Recrystallizing from ethyl acetate and petroleum ether reduced the yield to 5.4 g (70%). M.P. 107°-108.5°C. [ α]D25 = - 17.1° (C = 2, in ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Reactant: O=S(=O)(CCCCCCBr)NC1CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 67 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (435.2 mg, 1.52 mmol) and N-cyclopropyl-6-bromohexanesulfonamide (474.5 mg, 1.67 mmol) were refluxed in toluene (15 ml) in the presence of triethylamine (169 mg, 1.67 mmol) for 42 hours. The reaction mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (499.0 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 67.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 25 mL rbf was added 0.4137 g (1.31 mmol) of 4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-nitro-phenylamine, 4 mL of THF/EtOH (1:1). Vacuum flushed 3×, then added 0.1655 g of PtO2 (40% by weight) as a slurry in 2 mL of THF/EtOH (1:1). It was flushed with H2 3× and allowed to stir at r.t. for 18 h. 10 ml DCM and Celite was added and it was let stir 1 h. The mixture was then filtered through Celite pad, and the filter cake was rinsed with 20 mL DCM. The filtrate was reduced in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.85 (br. s., 1.7H) 5.31 (br. s., 1.7H) 6.62 (d, J=8.08 Hz, 1H) 7.19 (dd, J=8.08, 1.89 Hz, 1H) 7.26 (d, J=2.02 Hz, 1H) 7.66-7.70 (m, 2H) 8.02-8.06 (m, 2H). MS (m/z) 287.2 M (+1), tR=1.18, Meth 10
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([I:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[I-:24].[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N+:8]=2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2=NCCc3ccccc32)cc1
Reactant: ICc1ccccc1
Solvent: CC#N
Product: [I-]
Product: c1ccc(C[N+]2=C(c3ccccc3)c3ccccc3CC2)cc1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
A mixture of 1-phenyl-3,4-dihydroisoquinoline (1.0 g) and benzyliodide (1.26 g) in acetonitrile (7 ml) was refluxed for 1 hour. After allowing to cool to room temperature, the reaction mixture was evaporated in vacuo and the residual precipitate was recrystallized from a mixture of diethyl ether (5 ml) and acetonitrile (3 ml). The crystal was collected by filtration, washed with diethyl ether and dried in vacuo to give 1-phenyl-2-benzyl-3,4-dihydroisoquinolinium iodide (1.52 g).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=1>CN(C=O)C>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:14]2[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]3[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Ic1ccc2cn[nH]c2c1
Reactant: COc1ncccc1Nc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncccc1Nc1cc(-n2ncc3ccc(I)cc32)ncn1
Temperature: 110 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
To a solution of 6-iodo-1H-indazole (100 mg, 0.41 mmol) in DMF (5 mL) was added NaH (60% oil dispersion, 32.78 mg, 0.82 mmol)) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes before the addition of 6-chloro-N-(2-methoxypyridin-3-yl)pyrimidin-4-amine (126.7 mg, 0.55 mmol). The reaction mixture was then stirred at 110° C. for 18 hr. The reaction mixture was then cooled to RT, quenched by the addition of water (2 ml), EtOAc (a few drops) was added and the resultant precipitate was collected by suction filtration and thoroughly dried under high vacuum to give the title compound (120 mg, LC-MS: m/z=+444.90). This compound of 62% purity LC-MS (UV) was used without further purification.