Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:25]([NH:27][C@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)[CH3:29])=[O:26])[N:23]=[C:19]3[N:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:25]([NH:27][C@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)[CH3:29])=[O:26])[N:23]=[C:19]3[N:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: COc1cccc([C@H](C)NC(=O)Nc2nc3nccc(-c4ccc(OCc5ccccc5)cc4)n3n2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc([C@H](C)NC(=O)Nc2nc3nccc(-c4ccc(O)cc4)n3n2)c1

Procedure:
(S)-1-[7-(4-benzyloxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]-3-[1-(3-methoxyphenyl)ethyl]urea (the compound obtained in Example 222; 7.83 g) was dissolved in acetic acid (600 ml). Thereafter, 10% palladium carbon (50% water content; 2.0 g) was added to the solution, and the obtained mixture was stirred at 40° C. overnight in a hydrogen atmosphere. The reaction solution was filtrated with a filter medium (Celite), and the resultant was then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (eluted with 4% methanol-containing methylene chloride) to obtain the captioned compound (5.37 g).
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[S:7]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8]1.C1C[O:17][CH2:16]C1>>[S:7]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:5][C:2]([O:17][CH3:16])=[O:4])=[CH:8]1
Reactant: O=Cc1ccsc1
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: [K+]
Product: COC(=O)C=Cc1ccsc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of potassium t-butoxide (61.5 g, 0.55 mol) in THF (800 mL) was cooled in an ice bath and trimethylphospbonoacetate (98 mL, 0.60 mol) in THF (100 mL) was slowly added. After 45 min, thiophene 3-carboxaldehyde (50 mL, 0.55 mol) in THF (100 mL) was slowly added while stirred in the ice bath. The mi,suture was allowed to warm to rt and stirred for 16 h. The reaction was quenched with 5% sulfuric acid (300 mL) and extracted twice with ether. The organic layers were each washed with brine, dried over magnesium sulfate, combined and concentrated. The residue was purified by FC (10% ethyl acetate in hexanes) and then crystallized from hexanes to give the title compound (71.3 g).
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][C:39]2[CH:44]=[CH:43][C:42]([C@@H:45]3[CH2:47][C@H:46]3[C:48]([OH:50])=O)=[CH:41][CH:40]=2)=[CH:33][CH:32]=1.[OH-].[NH4+].O>CN(C=O)C.ClCCl>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][NH:38][C:39]2[CH:40]=[CH:41][C:42]([C@@H:45]3[CH2:47][C@H:46]3[C:48]([NH2:2])=[O:50])=[CH:43][CH:44]=2)=[CH:35][CH:36]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2ccc(-c3ccccn3)cc2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)[C@@H]1C[C@H]1c1ccc(NCc2ccc(-c3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
HATU (0.11 g, 0.29 mmol) and racemic-(trans)-2-[4-({[4-(2-pyridinyl)phenyl]methyl}amino)phenyl]cyclopropanecarboxylic acid (I-2c) (0.077 g, 0.22 mmol) in DMF (5 mL) were stirred at RT for 10 min, then ammonium hydroxide (2 mL) was added. The solution was stirred at RT for 16 h, then water (50 mL) and dichloromethane (50 mL) were added and the organic layer was separated, washed with water (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound as a white powder (0.029 g, 38%). 1H NMR (400 MHz, DMSO) δ8.64 (d, J=3.8 Hz, 1H), 8.02 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.0 Hz, 1H), 7.86 (t, J=7.9 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.33 (t, J=5.3 Hz, 1H), 6.81-6.79 (m, 3H), 6.50 (d, J=8.4 Hz, 2H), 6.19 (t, J=6.1 HZ, 1H), 4.30 (d, J=6.0 Hz, 2H), 2.05-2.00 (m, 1H), 1.64-1.60 (m, 1H), 1.20-1.15 (m, 1H), 1.03-0.98 (m, 1H). ES-MS m/z 344.2 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Cl:11][CH:12]([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]2.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(CC)CC)C>C(#N)C>[Cl:11][CH:12]([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]2.[ClH:11].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][N:36]([CH:17]([CH3:16])[C:18]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][C:2](=[O:10])[CH2:3]3)=[O:23])[CH2:35][CH2:34]1
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(Cl)Cc1ccc2c(c1)CC(=O)N2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1N1CCN(C(C)C(=O)c2ccc3c(c2)CC(=O)N3)CC1
Product: Cl
Reaction time: 3 h

Procedure:
5-(2-chloropropyl)-indolin-2-one was prepared from indolin-2-one according to the synthetic and working-up method of general procedure B. 5-(2-chloropropyl)-indolin-2-one (2.46 g, 0.011 mol) and 2-methoxyphenyl piperazine (1.92 g, 0.01 mol) were dissolved in 100 ml of acetonitrile, and triethyl amine (3.04 g, 0.03 mol) was added. A reaction under refluxing was allowed to proceed at an elevated temperature for 3 hours. Working up according to general procedure B gave 3.66 g of 5-(2-(4-(2-methoxyphenyl)piperazin-1-yl)propanoyl)indolin-2-one hydrochloride. The yield was 88.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].CNCC[C:23]1([NH2:32])[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][NH:24]1.[CH:33]([N:36](CC)[CH:37](C)C)(C)[CH3:34]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][CH:12]=[C:13]([N:36]([CH3:37])[CH2:33][CH2:34][NH:32][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNCCC1(N)C=CC([N+](=O)[O-])=CN1
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: CN(CCNc1ccc([N+](=O)[O-])cn1)c1ccc([N+](=O)[O-])c(-c2ccc(Cl)cc2Cl)c1
Temperature: 85 °C

Procedure:
To 22 mgs of 2-(2,4-dichlorophenyl)-4-fluoro-1-nitrobenzene in N,N-dimethylformamide was added 1–5 mgs of [2-(methylaminoethyl](5-nitro(2-pyridyl))-amine and 30 μl of N,N-diisopropylethylamine, and the mixture was heated to 85° C. over-night. After partitioning the mixture between ethyl acetate and water the organic layer was concentrated and dried (MgSO4) and recrystallized to yield 6 mgs of N-(2′,4′-dichloro-6-nitro-1,1′-biphenyl-3-yl)-N-methyl-N′-(5-nitropyridin-2-yl)ethane-1,2-diamine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21]([NH2:23])[CH3:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)(=[O:4])=[O:3].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C.O>C(O)CCC>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([NH:23][CH:21]([C:20]2[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:2]([CH3:1])(=[O:3])=[O:4])=[N:12][C:13]3[C:18]([CH:19]=2)=[N:17][CH:16]=[CH:15][CH:14]=3)[CH3:22])[N:28]=[CH:27][N:26]=1
Reactant: CC(N)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc(N)c1C#N)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of crude 1-(2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethanamine (600 mg, 1.83 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (283 mg, 1.83 mmol) in n-butanol (11 mL) was added Hunig base (709 mg, 5.49 mmol) at 25° C. The reaction mixture was stirred for overnight at 110° C. Water was added to reaction mixture and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on neutral alumina using 0-5% MeOH in DCM. It was further purified by reversed-phase HPLC to give 4-amino-6-((1-(2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethyl)amino)-5-pyrimidine-carbonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 1.387 (d, J=6.8 Hz, 3H), 5.250-5.322 (m, 1H), 7.246 (br s, 2H), 7.735-7.843 (m, 3H), 7.911-7.940 (m, 3H), 8.110-8.129 (m, 1H), 8.395 (d, J=4.4 Hz, 1H), 8.622 (s, 1H), 9.028-9.074 (m, 1H); LC-MS (ESI) m/z 446.0 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]([CH2:16]CO)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C.[CH:24]([Cl:27])(Cl)Cl>>[ClH:3].[Cl:3][CH2:6][CH2:7][N:8]([CH2:16][CH2:24][Cl:27])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCN(CCO)Cc1ccccc1
Reactant: ClC(Cl)Cl
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: Cl
Product: ClCCN(CCCl)Cc1ccccc1
Temperature: 25 °C

Procedure:
Thionyl chloride (25.4 g, 130 mmol) and chloroform (20 mL) are combined. A solution of N,N-bis(2-hydroxyethyl)-N-benzylamine (25.4 g, 130 mmol) in chloroform (20 mL) is added dropwise over 1 hour. When the addition is complete the reaction mixture is refluxed for 1 hour. The reaction mixture is cooled to ambient temperature and diethyl ether was added to form a solid which is collected by filtration, rinsed with diethyl ether, and dried to give the title compound.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:8]([C:10]1[CH:11]=[C:12]([CH:16]2[NH:20][CH2:19][CH:18]([CH2:21][CH3:22])[O:17]2)[CH:13]=[CH:14][CH:15]=1)#[N:9].N1C=CC=CC=1>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[C:12]([CH:16]2[N:20]([C:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:19][CH:18]([CH2:21][CH3:22])[O:17]2)[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: CCC1CNC(c2cccc(C#N)c2)O1
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1CN(C(=O)CC(C)C)C(c2cccc(C#N)c2)O1
Reaction time: 8 h

Procedure:
Two and five-tenths grams of isovaleroyl chloride in 10 ml of methylene chloride was added dropwise to 6.5 g of 2-(m-cyanophenyl)-5-ethyl-1,3-oxazolidine in 25 ml of methylene chloride containing 1.9 g of pyridine. The mixture was allowed to stir overnight, washed with 50 ml of 5% NaOH and 200 ml of water, dried over anhydrous MgSO4 and stripped on the rotary evaporator. The yield was 3.7 g, nD30 1.5455. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Li]CCCC.[Si:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]I)=[CH:26][CH:25]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>C1COCC1.CCOCC>[Si:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:26][CH:25]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CI)cc1
Reactant: C#CCCCCCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC#CCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 1; -nonyne (150 mg, 1.2 mmol) in THF (5 mL) at -78° C., was added n-BuLi (0.47 mL, 1.19 mmol). The resulting mixture was stirred for 30 minutes and a solution of [(tertButyldimethylsilyl)oxymethyl]-4-iodomethyl benzene (40) (361 mg, 2 mmol) in THF (1 mL) was added. The reaction mixture was then stirred at -78° C. for 1 hour, allowed to warm to 0° C. and stirred for an additional 30 minutes. At this time, water (2 mL) was slowly added and the mixture was poured into water (50 mL) and Et2O (50 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield a yellow oil. Purification by flash silica gel chromatography (95:05 hexane/EtOAc) afforded (51) (313 mg, 87%) as a colorless oil: Rf 0.85 (95:05 hexane/EtOAc); 1H NMR (CDCl3) δ 7.34 (d, J=8.7 Hz, 2 H), 7.29 (d, J=7.8 Hz, 2 H), 4.75 (s, 2 H), 3.59 (t, J=2.4 Hz, 2 H), 2.24 (tt, J1 =7.2 Hz, J2 =2.4 Hz, 2 H), 1.55 (m, 2 H), 1.42 (m, 2 H), 1.32 (m, 6 H), 0.97 (s, 9 H), 0.92 (t, J=6.9 Hz, 3 H), 0.12 (s, 6 H); 13 C NMR (CDCl3) δ 139.68, 136,38, 127.83, 126.32, 82.74, 77.76, 64.93, 31.91, 29.18, 29.98, 26.08, 24.97, 22.77, 18.97, 14.23, -5.11. ##STR25##
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(OC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(CC(=O)O)cc1
Yield: 95.5 %

Procedure:
Methyl 2-(4-isopropoxyphenyl)acetate (10 g, 48.0 mmol), and NaOH (5.76 g, 144 mmol) were heated in methanol (50 mL)/Water (50 mL) solution at reflux for 2 h. Most of the MeOH was removed under vacuum and the remaining aqueous solution was acidified with 1 N HCl. The solid that precipitated from the solution was extracted into EtOAc solution. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum to give 2-(4-isopropoxyphenyl)acetic acid (8.9 g, 95% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.16 (m, 2H), 6.88-6.83 (m, 2H), 4.53 (spt, J=6.1 Hz, 1H), 3.59 (s, 2H), 1.34 (d, J=6.0 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[C:7]2[C:8]([O:10][C:11](=O)[NH:12][C:6]2=[CH:5][CH:4]=1)=[O:9].[NH:17]([CH2:19]C(O)=O)[CH3:18].O>CS(C)=O>[CH3:18][N:17]1[C:8](=[O:9])[C:7]2[CH:14]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:4]=[CH:5][C:6]=2[NH:12][C:11](=[O:10])[CH2:19]1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2c(=O)o1
Reactant: CNCC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccc(C(F)(F)F)cc2C1=O
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A suspension of 5.76 g (24.9 mmole) of 5-(trifluoromethyl)isatoic acid anhydride and 2.44 g (27.4 mmol) of sarcosine in 8 ml of dimethyl sulphoxide is stirred at 110° C. for 4 hours, subsequently poured into 70 ml of water and evaporated to dryness in vacuo. After column chromatography on silica gel using ethyl acetate/n-hexane (9:1) for the elution and recrystallisation of the product from ethanol, there is obtained 3,4-dihydro-4-methyl-7-(trifluoromethyl)-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 203°-206° C.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][C:40]1[CH:58]=[CH:57][C:43]([CH2:44][N:45]2[CH2:50][CH2:49][CH:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:47][CH2:46]2)=[CH:42][CH:41]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[C:51]1([CH:48]2[CH2:47][CH2:46][N:45]([CH2:44][C:43]3[CH:57]=[CH:58][C:40]([CH2:39][NH:38][C:13]([C:5]4[S:6][C:7]5[N:12]6[C:3](=[CH:2][N:1]=[C:11]6[CH:10]=[CH:9][CH:8]=5)[CH:4]=4)=[O:15])=[CH:41][CH:42]=3)[CH2:50][CH2:49]2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NCc1ccc(CN2CCC(c3ccccc3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(NCc1ccc(CN2CCC(c3ccccc3)CC2)cc1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 1 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 0.90 g (7.82 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.51 g (7.88 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature, and the mixture was stirred for 1 hour. To this reaction mixture was added a solution of 1.67 g (4.73 mM) of 1-[4-(aminomethyl)benzyl]-4-phenylpiperidine dihydrochloride, 1.44 g (9.46 mM) of DBU, and 0.55 ml (3.95 mM) of triethylamine in acetonitrile (20 ml), and the mixture was further stirred for 4 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with ethyl acetate (a small amount of ethanol was additionally used). The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. This crude product was purified by column chromatography (methanol/ethyl acetate 20-30%) to provide the title compound as red amorphous substance.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28]([C:34]([F:37])([F:36])[F:35])(C(O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC.[CH2:45]([OH:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[N-:53]=[C:54]=[O:55]>C1(C)C=CC=CC=1>[CH2:45]([O:52][C:54]([NH:53][C:28]1([C:34]([F:35])([F:36])[F:37])[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24])[CH2:30][CH2:29]1)=[O:55])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: OCc1ccccc1
Reactant: [N-]=C=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(C(F)(F)F)CC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(F)(F)F)CC1
Temperature: 80 °C

Procedure:
Diphenylphosphoryl azide (1.1 equiv.) is added to a solution of 1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine-4-carboxylic acid (3c) (1 equiv.) and Et3N (1 equiv.) in dry toluene at room temperature, and the reaction is warmed gradually to 80° C. The reaction is kept at 80° C. until gas evolution stops, then dry benzyl alcohol (2 equiv.) is added. The reaction is stirred at 80° C. until the isocyanate is consumed, then the solvents are removed in vacuo. The residue is taken up in CH2Cl2 and the solution is washed sequentially with dilute HCl, dilute NaOH, and H2O. The solution is dried (MgSO4) and concentrated in vacuo, and the residue is purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[NH:14][C:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[C:12]([CH3:23])[C:10]3=2)[NH:5][C:4](=[O:24])[CH:3]=1.[F:25][C:26]([F:31])([F:30])[C:27](O)=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[N:14]([CH2:27][C:26]([F:31])([F:30])[F:25])[CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH:12]([CH3:23])[C:10]3=2)[NH:5][C:4](=[O:24])[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(-c2[nH]c3ccc4[nH]c(=O)cc(Cl)c4c3c2C)cc1
Product: COc1ccc(C2C(C)c3c(ccc4[nH]c(=O)cc(Cl)c34)N2CC(F)(F)F)cc1

Procedure:
This compound was prepared using the method described in Example 23 from 9-Chloro-2-(4-methoxy-phenyl)-1-methyl-3,6-dihydro-pyrrolo[3,2-f]quinolin-7-one, and trifluoroacetic acid. Spectral data for compound 148: 1H NMR (500 MHz, acetone-d6) δ 7.48 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.7 Hz, 2H), 6.74 (s, 1H), 5.01 (d, J=8.1 Hz, 1H), 4.29 (m, 1H), 4.15 (dq, J=16.3, 10.0 Hz, 1H), 3.88 (s, 3H), 3.73 (dq, J=16.3, 9.3 Hz, 1H), 0.92 (d, J=7.2 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].N1C=CC=CC=1.[C:19]12([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=3[O:38][CH3:39])[C:32](Cl)=[O:33])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2.CCCCCC>ClCCl>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]([NH:6][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:29]([C:19]34[CH2:28][CH:23]5[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]5)[CH2:26]3)[CH2:20]4)[CH:30]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCCCCC
Product: COc1ccc(NC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c([N+](=O)[O-])c1
Yield: 90 %

Procedure:
5.38 g (32 mM) of 2-nitro-4-methoxyaniline and 50 ml of pyridine are introduced into a round-bottomed flask. 9.7 g (32 mM) of 3-(1-adamantyl)-4-methoxybenzoic acid chloride, dissolved in 100 ml of dichloromethane, are then added dropwise. At the end of addition, the mixture is brought to reflux for 12 hours. After having cooled, 100 ml of hexane are added and the precipitate obtained is recovered by filtration and washed with a mixture containing 10% ether and 90% hexane and then with water. After drying, there are obtained 12.5 g (89%) of the expected product. M.p.=208°-210° C.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[CH3:27][O:28][C:29]1[CH:45]=[CH:44][C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=2[CH2:42]O)=[CH:31][CH:30]=1>C(Cl)Cl.C1COCC1>[I:25][CH2:42][C:36]1[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:35]=1[O:34][CH2:33][C:32]1[CH:44]=[CH:45][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1
Reactant: II
Reactant: COc1ccc(COc2ccc(C)cc2CO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C)cc2CI)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of imidazole (1.52 g, 22.32 mmol) and triphenylphosphine (5.85 g, 22.32 mmol) in methylene chloride (30 mL)/THF (15 mL) is added iodine (5.67 g, 22.32 mmol) in portions and the mixture is stirred at RT for 3 h. To this is added dropwise a solution of [2-(4-methoxybenzyloxy)-5-methylphenyl]-methanol (4.80 g, 18.6 mmol) in THF (15 mL) and the mixture is stirred at RT for 18 h. The mixture is concentrated and the insoluble material is filtered. The filtrate is evaporated and the residue is purified by column chromatography using a gradient of 0-75% EtOAc/hexane as eluent to give the title compound as a brown oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=CC=CN=2)CCCC1.Cl[C:38]([O:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[O:39]>N1C=CC=CC=1>[CH2:41]([O:40][C:38]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)(=[O:24])=[O:23])=[O:39])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CC(C)COC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
30 mg of crude 3(4-imidazol-1-ylmethylphenyl)5-iso-butylthiophene-2-sulfonamide (see Example 1(f) above) was dissolved in pyridine (1 mL, dried over 4 Å molecular sieve) and cooled on ice. Pyrrolidinopyridine (11.8 mg, 0.080 mmol) and iso-butyl chloroformate (103.6 μL, 0.80 mmol) were then added to the mixture. The mixture was stirred overnight under a N2 atmosphere at 50° C. Evaporation and co-evaporation with acetonitrile to remove the solvents, followed by purification by column chromatography using 10% MeOH in CHCl3 as eluent gave the title compound (27 mg, 0.057 mmol) in 71% yield.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1.[CH2:21]([N:23]([CH2:26]C)CC)[CH3:22].CSC(SC)=C[N+:32]([O-:34])=[O:33].CN>O>[NH2:19][C:18](=[N:17][C:14]1[S:15][CH:16]=[C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][NH:4][C:21]([NH:23][CH3:26])=[CH:22][N+:32]([O-:34])=[O:33])[N:11]=2)[N:13]=1)[NH2:20]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (1.7 g), triethylamine (2.0 ml) and 1,1-bis(methylthio)-2-nitroethylene (0.9 g) was stirred at 70° C. for 7 hours. After cooling to ambient temperature, to the mixture was added a 40% aqueous methylamine (2.5 ml) and the mixture was stirred at ambient temperature for 15 hours. The reaction mixture was added to water, and the isolated precipitate was collected by filtration and dried. 4N-Dioxanoic hydrogen chloride (2.2 ml) was added to a mixture of above resulting precipitate in methanol (9.0 ml) and the mixture was stirred at ambient temperature for 1 hour. To the mixture was added a diisopropyl ether (9.0 ml) and the isolated precipitate was collected by filtration. The precipitate was recrystallized from an aqueous ethanol to give 2-(diaminomethyleneamino)-4-[6-[N-(1-methylamino-2-nitrovinyl)aminomethyl]pyridin-2-yl]thiazole (0.47 g).