Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:43][NH:44][C:45]([C:47]1[C:48]([CH3:60])=[N:49][C:50]([CH3:59])=[CH:51][C:52]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:46]>CN(C=O)C>[CH3:43][NH:44][C:45]([C:47]1[C:48]([CH3:60])=[N:49][C:50]([CH3:59])=[CH:51][C:52]=1[N:53]1[CH2:58][CH2:57][N:56]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:55][CH2:54]1)=[O:46]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: CNC(=O)c1c(N2CCNCC2)cc(C)nc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)cc(C)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (21 mg, 0.15 mmol) was dissolved in anhydrous DMF (1 ml), diisopropylethylamine (52 μl, 0.3 mmol) was added followed by HBTU (60 mg, 0.15 mmol) and the mixture was stirred at room temperature for 15 minutes. N,2,6-trimethyl-4-piperazin-1-yl-pyridine-3-carboxamide (37.2 mg, 0.15 mmol) was dissolved in a mixture of DMF (0.5 ml) and diisopropylethylamine (26 μl, 0.15 mmol) and the resulting solution was added to the solution of the activated carboxylic acid. The resulting mixture was stirred at room temperature for three hours, the solvent was removed under reduced pressure and the raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 21.4 mg of a solid (0.058 mmol, 38%).
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].CN(C)[CH:9]=[CH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH:2]([N:5]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)NN
Reactant: CCOC(=O)C(=O)C=CN(C)C
Agent: Cl
Product: CCOC(=O)c1ccn(C(C)C)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using isopropylhydrazine hydrochloride and ethyl 4-(Dimethylamino)-2-oxobut-3-enoate at 120° C. for hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 2.5-40%). tR: 3.73 min (HPLC 1); tR: 0.80 min (LC-MS 2); ESI-MS: 183 [M+H]+ (LC-MS 2); Rf=0.69 (hexane/EtOAc 1:1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Yield: 100.8 %

Procedure:
Using 4-bromo-2-fluorobenzoic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4.4 g) and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (9 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:13]([C:14]1[O:10][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:15])[CH3:12]
Reactant: CC(=O)CCl
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2cc(Br)ccc2o1
Temperature: 60 °C
Yield: 69.5 %

Procedure:
A mixture of 5.0 g (24.9 mmol) of 5-bromo-salicylaldehyde, 3.0 g (32.3 mmol, 2.6 mL) of chloroacetone and 12 g (37.2 mmol) of Cs2CO3 in 30 mL of dry DMF was heated to 60° C. overnight. After cooling at room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was directly recrystallized from hexane to afford 4.14 g (17.3 mmol, yield: 70%) of 2-acetyl-5-bromo benzo[b]furan as a pale orange crystal. 1H NMR (CDCl3), δ: 7.84 (d, J=1.9 Hz, 1H), 7.56 (dd, J=9.0, 2.1 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.42 (s, 1H), 2.60 (s, 3H).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].O.[NH2:18][C@@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:18][C@@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a mixture of Boc-Leu-OH.H2O (2.5 g), H-DTrp-OBzl (2.9 g) and HOBT.H2O (1.6 g) in dichloromethane (50 ml) was added EDCI.HCl (2.0 g) under ice cooling. After being stirred at room temperature for 16 h, the mixture was washed with water, 10% aq. citric acid, sat. aq. NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was triturated with hexane to give Boc-Leu-DTrp-OBzl (4.79 g). To a solution of the dipeptide (753 mg) in dichloromethane (7 ml) were added methyl chloroformate (1 ml), pulverized NaOH (89 mg) and TBAHS (20 mg) under ice cooling. After being stirred of the mixture at room temperature for 30 min, pulverized NaOH (89 mg) was added. This procedure was repeated twice more. The reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3, 10% aq. citric acid, water and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was recrystallized from dichloromethane and petroleum ether to give Boc-Leu-DTrp(COOMe)-OBzl (721 mg) as colorless crystals. The dipeptide (708 mg) was dissolved in methanol (7 ml)--THF (5 ml) and 10% Pd/C (70 mg) was added. The mixture was vigorously stirred at room temperature under an atmospheric pressure of hydrogen for 1 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give Boc-Leu-DTrp(COOMe)-OH (580 mg).
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13](=O)CC)(=[O:11])[CH2:9][CH3:10].CN([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]N=1)C.C(C(CC)C=O)C>CCCCCC.O>[C:8]([O:12][CH:13]=[C:24]([CH2:25][CH3:20])[CH2:23][CH3:22])(=[O:11])[CH2:9][CH3:10]
Reactant: CN(C)c1ccccn1
Reactant: CCC(=O)OC(=O)CC
Agent: CCC(C=O)CC
Solvent: CCCCCC
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)OC=C(CC)CC
Temperature: 70 °C

Procedure:
A reaction vessel was charged sequentially with Et3N (12.8 L), propionic anhydride (14.48 L), dimethylaminopyridine (94 gm) and 2-ethylbutyraldehyde (7.5 L). The mixture was stirred and heated under gentle reflux (120°-135° C.) for 5 hours in a nitrogen atmosphere. The reaction was then cooled to 70° C. and H2O (13.5 L) was added slowly. On complete addition, the mixture was heated at reflux for 45 minutes and then cooled to room temperature before hexane (7.5 L) was added. The aqueous layer was separated and re-extracted with hexane (5 L) and the combined organic layers were washed with saturated NaHCO3 (2×7.5 L) before being evaporated in vacuo at 40° C. The residue (10 Kg) so obtained was fractionally distilled (b.p. 75°-80° C., 30-40 mm Hg) to give the required product (7.712 Kg) as a mobile liquid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([OH:24])[CH:22]=2)[N:17]=[CH:16][N:15]=1.O[C@H:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:30]([C:41]([O:43][CH3:44])=[O:42])[CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([O:24][C@@H:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C@H:30]([C:41]([O:43][CH3:44])=[O:42])[CH2:29]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Cl)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Yield: 79 %

Procedure:
A solution of DEAD (0.329 ml, 2.08 mmol) in DCM (2 ml) was added to as stirred suspension of 4-chloro-7-methoxyquinazolin-6-ol (283 mg, 1.74 mmol prepared as described in Example 16 of WO03/082831),1-tert-butyl 2-methyl (2S,4S)-4-hydroxypiperidine-1,2-dicarboxylate (11) (450 mg, 2.08 mmol) and triphenylphosphine (547 mg, 2.098 mmol) in DCM (10 ml), such that the internal temperature remained <30° C. The reaction mixture was stirred overnight and evaporated to dryness. The residues were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give 1-tert-butyl 2-methyl (2S,4R)-4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1,2-dicarboxylate (12) as a gum (478 mg, 79%): 1H NMR Spectrum: (DMSO-d6) δ1.39-1.46 (10H, m), 1.73-1.84 (1H, m), 1.92-2.03 (1H, m), 2.10-2.18 (1H, m), 2.60-2.69 (1H, m), 3.15-3.40 (3H, m), 3.74-3.85 (1H, m), 4.01 (3H, s), 4.61-4.73 (1H, m), 5.06 (1H, s), 7.43 (1H, s), 7.47 (1H, s), 8.89 (1H, s), 8.97 (1H, s); Mass Spectrum: (M+H)+ 452.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[S:10][CH2:9][CH2:8]C(C#N)(O[Si](C)(C)C)[C:6]=2[CH:18]=1.[C:20]([OH:23])(=[O:22])[CH3:21]>>[ClH:1].[Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[S:10][CH2:9][CH2:8][CH:21]([C:20]([OH:23])=[O:22])[C:6]=2[CH:18]=1
Reactant: CC(=O)O
Reactant: C[Si](C)(C)OC1(C#N)CCSc2cc(Cl)c(Cl)cc21
Product: Cl
Product: O=C(O)C1CCSc2cc(Cl)c(Cl)cc21

Procedure:
Following the procedure of Example 2, 6,7-dichloro-4-cyano-4-trimethylsilyloxy-3,4-dihydro-2H-1-benzothiopyran (7.5 g.) and stannous chloride dihydride (30 g.) were reacted in glacial acetic acid (30 ml.) and concentrated hydrochloric acid (30 ml.) to form 6,7-dichloro-3,4-dihydro-2H-1-benzothiopyran-4-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][C:3]([CH3:24])([CH3:23])[CH2:2][NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CNS(C)(=O)=O

Procedure:
Using the general method of Example 242, 1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.22 g, 0.672 mmol) was reacted with methanesulfonyl chloride (125 μL) to provide 270 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}methanesulfonamide as a cream colored powder, m.p. 204.0-206.0° C. Analysis: Calculated for C19H27N5O3S.0.50 H2O: %C, 55.05; %H, 6.81; %N, 16.89; %S, 7.74; Found: %C, 55.10; %H, 6.58; %N, 17.23; %S, 7.51. % H2O calculated: 2.17; found: 2.28 (Karl Fisher).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[CH:11]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N:25]2[CH2:30][CH2:29][N:28](CCC3C=C(C=CC=3)N)[CH2:27][CH2:26]2)[N:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N:25]2[CH2:30][CH2:29][N:28]([CH2:11][CH:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH3:13])[CH2:27][CH2:26]2)[N:16]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CC(C=O)c1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(CC(C)c4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Reaction time: 1 h
Yield: 133.1 %

Procedure:
A mixture of 2-(3-nitrophenyl)propanal (1.2 equiv. 50 mg), 2-methyl-5-(1-piperazinyl)quinoline (D3) (52 mg) and DCM (2 mL) was stirred for 1 h. Sodium triacetoxyborohydride (1.2 equiv., 58 mg) was added and the resulting mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo and purified using ion-exchange chromatography (SCX-2), eluting with methanol followed by ammonia in methanol (1M). The basic fractions were concentrated under vacuum and purified by chromatography (SPE, SiO2) using DCM-methanol (98:2) as eluent to afford the title compound as yellow liquid (78 mg, 78% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)c1
Reactant: c1c[nH]cn1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3ccnc3)nc3sc4c(c23)CCCC4)c1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:17])[CH2:11][NH:12][CH:13]([C:15]#[N:16])[CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18](Cl)(=[O:22])[C:19]([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:1][C:15]1[N:16]=[C:19]([Cl:21])[C:18](=[O:22])[N:12]([CH2:11][C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:17])[C:13]=1[CH3:14]
Reactant: Cl
Reactant: CC(C#N)NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 41 %

Procedure:
A suspension of benzyl-2-[(1-cyanoethyl)amino]acetate hydrochloride (preparation 16) (17.8 g, 69.88 mmol) in toluene (120 ml) was treated cautiously with oxalyl chloride (24.38 ml). Once effervescence had ceased the reaction was heated at 100° C. (24 hr). The reaction was cooled, solvent evaporated to dryness and the resultant crude product purified by chromatography (SiO2, gradient elution with 70:30 pentane:ethyl acetate; 50:50 pentane:ethyl acetate; 30:70 pentane:ethyl acetate; 100% ethyl acetate). Chromatography again, (SiO2, eluting with 100% CH2Cl2) gave the desired product as an off-white solid (9.40 g, 41%). 1H NMR (CD3OD) δ 2.35 (s, 3H), 4.90 (s, 2H), 5.25 (s, 2H), 7.40 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>ClCCl>[C:10]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=1[Br:1])(=[O:12])[CH3:11]
Reactant: Oc1cccc(O)c1Br
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1cccc(O)c1Br

Procedure:
To a solution of 2-bromo-1,3-benzenediol (3.028 g, 16.02 mmol) in dichloromethane (70 ml), TEA (3.35 ml, 24.03 mmol) and acetic anhydride (1.512 ml, 16.02 mmol) were added under stirring. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with a saturated solution of ammonium chloride (100 ml), and extracted with ethyl acetate (3 times 70 ml). The combined organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound as a black oil which was used directly used in the next step. (3.028 g)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:44]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH3:26])=[CH:27][CH:28]=2)=[CH:11][CH:10]=1)[CH2:44][C:40]1[NH:39][CH:43]=[CH:42][N:41]=1
Reactant: CCCN(CCC)Cc1ccc(OCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(OCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The compound (20.4 mg) obtained in Example 35-5 was dissolved in anhydrous methanol (2.0 ml) and added with sodium cyanoborohydride (9.50 mg), acetic acid (2.0 ml), and 2-imidazole carboxaldehyde (9.60 mg), followed by stirring at room temperature under a nitrogen atmosphere for 6.5 hours and a half. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. Subsequently, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, and the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (4.50 mg) of the subject compound as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][CH2:12]O)=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[CH3:23][S:24]([O:27]S(C)(=O)=O)(=O)=[O:25].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:42]2[NH:43][C:44]3[C:49]([C:50]=2[CH2:51][CH2:52][NH2:53])=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:42]2[NH:43][C:44]3[C:49]([C:50]=2[CH2:51][CH2:52][NH:53][CH2:12][CH:11]=[CH:10][C:8]2[CH:7]=[CH:6][C:5]4[N:1]([S:24]([CH3:23])(=[O:27])=[O:25])[CH:2]=[N:3][C:4]=4[CH:9]=2)=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCN)cc1OC
Reactant: OCC=Cc1ccc2[nH]cnc2c1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNCC=Cc2ccc3c(c2)ncn3S(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(1H-benzoimidazol-5-yl)-prop-2-en-1-ol (44 mg in a mixture of 2 mL methylene chloride and 0.1 mL N,N-dimethylformaminde) at 0° C. was added sequentially 346 mg of tetrabutylammonium bromide, 0.110 mL diisopropylethylamine, and 100 mg methanesulfonic anhydride and the mixture allowed to warm to room temperature. After 1 hour, this mixture was added to a solution of 2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]-ethylamine (300 mg in a mixture of 6 mL methylene chloride and 1.5 mL N,N-dimethylformamide) and stirring continued for 2.5 hours. At this time the mixture was concentrated in vacuo and the residue purified by flash chromatography on silica gel (methylene chloride:methanol, 91:9) to give the title compound (24 mg).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=1.CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[Cl:10][C:11]1[CH:23]=[C:22]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])[C:14]([C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])=[CH:13][N:12]=1
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CCN(CC)C(=O)c1ccc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)C(=O)c1cnc(Cl)cc1-c1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
7.62 ml (7.62 mMol) o-Tolylmagnesium chloride solution (1M in THF) were added over 15 minutes to a solution of 0.60 g (2.54 mMol) 6-chloro- N,N-diethyl-nicotinamide in 3.0 ml THF cooled to 0° C. The reaction mixture was stirred 2 hours at room temperature, then cooled again to 0° C. and 0.41 ml methanol (10.1 mMol) were added followed by 692 mg 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.1 mMol). After stirring 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure and 50 ml t-butyl-methylether were added at 50° C. The resulting suspension was filtered off, the filtrate was concentrated and the residue was purified by flash chromatography (eluent: ethyl acetate/n-heptane 1:1) to yield 0.67 g (86%) of 6-chloro-N,N-diethyl-4-o-tolyl-nicotinamide as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].ClCCl>O>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:6][CH2:5]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(CCO)CC1

Procedure:
A mechanically-stirred solution of 1-(2-hydroxyethyl)piperazine (10.0 g, 9.4 mL, 0.07 mol) in 30 mL of deionized water is cooled to 0 C. Then portions of 4N sodium hydroxide (total 28 mL) and portions of benzyl chloroformate (18.8 g, 15.7 mL, 0.11 mol) are added over 15 minute periods, keeping the temperature at 0 C. to 5 C. At the end of the additions, 4N sodium hydroxide solution is added to bring the pH of the reaction mixture to 10. After 1 hour dichloromethane (200 mL) is added and the layers are separated. The organic solution is dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1-(2-hydroxyethyl)-4-carbobenzyloxypiperazine.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([SH:9])([CH3:8])[CH3:7].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1.C([O-])(O)=O.[Na+]>C(O)C>[C:6]([S:9][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1)([CH3:8])([CH3:7])[CH3:5]
Reactant: CC(C)(C)S
Reactant: N#Cc1ccc(Cl)nc1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)Sc1ccc(C#N)cn1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Add sodium ethoxide (12 mL of 21% w/v in ethanol, 36 mmol) to a solution of 2-methyl-2-propanethiol (4.06 mL, 36 mmol) in anhydrous ethanol (90 mL) at 0° C. under nitrogen atmosphere. Stir the solution and allow it to warm to room temperature over 30 min. Add 6-chloronicotinonitrile (5 g, 36 mmol) and then heat the reaction to reflux overnight. Cool to room temperature, add saturated aqueous NaHCO3 and concentrate in vacuo. Extract into EtOAc or dichloromethane and wash with brine. Dry over MgSO4 and concentrate in vacuo to give the desired intermediate as orange crystals (6.31 g, 91%). MS (ES+) m/z: 193 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25]
Reactant: CC1CCCN1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CC1CCCN1C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and 2-methyl-pyrrolidine. MS (ESI): 426.3 (MH+).