Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([C@@H:13](O)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=CC=2)=[O:12])[CH2:7][CH2:6]1.[H-].[Na+].Br[C@H:25]([CH2:29][CH2:30][CH2:31][CH3:32])[C:26]([OH:28])=[O:27].C1C[O:36][CH2:35][CH2:34]1>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([C@@:13]2([CH2:34][CH2:35][O:36][C@@H:25]([CH2:29][CH2:30][CH2:31][CH3:32])[C:26]([OH:28])=[O:27])[CH:18]=[CH:19][CH:20]=[CH:15][CH2:14]2)=[O:12])[CH2:9][CH2:10]1
Reactant: C1CCOC1
Reactant: CCCC[C@@H](Br)C(=O)O
Reactant: COCOC1CCN(C(=O)[C@@H](O)Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC[C@H](OCC[C@]1(C(=O)N2CCC(OCOC)CC2)C=CC=CC1)C(=O)O
Temperature: 45 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
1(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-2-phenylethanol (European Patent Application No. EP364804, published Apr. 25, 1991) (43.13 g, 147.2 mmol) in 200 mL dry THF was added dropwise to the suspension of sodium hydride (60% dispersion in oil, 12.36 g, 309.1 mmol) in 136 mL dry THF and 22.7 mL DMF at 45° C. oil bath temperature under N2 atmosphere. The addition took approximately 1 h. The mixture was allowed to stir at 45° C. for additional 3 h. The gray suspension turned white after stiring for an hour and became very viscous. An additional 36 mL of dry THF was added to facilitate stirring. A solution of (R)-2-bromohexanoic acid (31.57 g, 161.9 mmol) in 180 mL THF was added dropwise to the thick, white suspension at 45° C. The addition took approximately 1.75 h. The suspension was removed from the oil bath 45 min after addition was completed and quenched immediately with careful addition of 120 mL of pH 7 phosphate buffer (0.3 M). The solution was then concentrated under reduced pressure at 35° C. and the resulting liquid extracted with 3×100 mL of diethyl ether to remove the unreacted alcohol. The aqueous phase was mixed with 300 mL of CH2Cl2 and acidified to pH 2 with 200 mL of 1 M sodium hydrogen sulfate. The layers were shaken and separated, then the aqueous phase was extracted with 2×300 mL of CH2Cl2. The combined organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 1.5% HOAc-5% iPrOH-35% THF-hexane) to obtain 36.35 g (88.32 mmol, 60%) of the desired compound as a low-melting solid: Rf 0.30 (EtOAc-hexane 5:2); 1H NMR (CDCl3) δ 0.8 (d, 3 H), 0.95 (m, 5 H), 1.2-1.9 (m, 22 H), 3.0 (q, 2 H), 3.2 (m, 4 H), 3.55 (m, 2 H), 3.65 (m, 2 H), 3.8 (t, 1 H),4.4 (q, 1 H), 7.3 (m, 5 H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH:11](Br)([CH3:13])[CH3:12].[CH3:15][C:16]([O-])(C)[CH3:17].[K+]>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[N:6]=[CH:5]2.[I:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH:16]([CH3:17])[CH3:15])[N:7]=2)[CH:3]=1
Reactant: CC(C)Br
Reactant: Ic1ccc2[nH]ncc2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1cc2cc(I)ccc2n1
Product: CC(C)n1ncc2cc(I)ccc21
Reaction time: 8 h
Yield: 40 %
Yield: 52 %

Procedure:
A mixture of 5-iodo-1H-indazole (488 mg, 2 mmol), isopropyl bromide (244 mg, 2 mmol), and KOtBu (336 mg, 3 mmol) in dry DMF (4 ml) was stirred at room temp. overnight. Then it was diluted with ethyl acetate (50 ml), washed with water (2×50 ml), and dried with Na2SO4. Evaporation of solvent and purification by flash chromatography on silica gel (n-heptane/ethyl acetate) afforded the subtitle compound (298 mg, 52%) along with 5-iodo-2-isopropyl-2H-indazole (227 mg, 40%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[O:33][C:34]([CH:37]=O)=[CH:35][CH:36]=2)=[CH:4][N:3]=1.[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][NH:44][CH3:45]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[O:33][C:34]([CH2:37][N:44]([CH2:43][CH2:42][CH2:41][N:40]([CH3:46])[CH3:39])[CH3:45])=[CH:35][CH:36]=2)=[CH:4][N:3]=1
Reactant: CNCCCN(C)C
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(-c4ccc(CN(C)CCCN(C)C)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-{4-[4-amino-7-(5-formyl-2-furyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide, N,N,N′-trimethylpropane-1,3-diamine and the procedure described in General Procedure B. 1H NMR (DMSO-d6, 400 MHz) δ 9.53 (s, 1H), 8.31 (s, 1H), 8.01 (d, 1H), 7.71 (d, 1H), 6.67 (s, 1H), 7.59 (d, 1H), 7.36 (s, 1H), 7.32 (m, 1H), 7.22 (s, 1H), 7.15 (m, 1H), 7.11 (m, 1H), 6.80 (m, 1H), 6.49 (m, 1H), 5.63 (br, 2H), 4.04 (s, 3H), 3.92 (s, 3H), 3.66 (s, 2H), 2.43 (m, 2H), 2.35 (s, 6H), 2.26 (s, 3H), 2.19 (m, 2H), 1.96 (m, 2H); MS: (M−H)− 621.
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])O.[Na+].CN(C)C=O.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:1]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(CC(=O)OCC)Cc1ccccc1
Yield: 101 %

Procedure:
Into a 5-L three-necked flask, 523.2 g (2.765 moles) of diethyl iminodiacetate, 465.4 g (5.540 moles) of sodium hydrogencarbonate and 1.4L of DMF (dimethylformamide) were put, and, keeping the mixture at about 40° C., 473.5 g (2.768 moles) of benzyl bromide was slowly dropwise added thereto with stirring. Thereafter, the mixture was stirred at about 40° C. for 16 hours. After the reaction was completed, 1.5L of water was added to the reaction product, which was then extracted with toluene (500 ml×four times). The organic layer formed was washed with water and dried with Glauber's salt. Thereafter, the solvent was evaporated to dryness to obtain 780 g of diethyl N-benzyliminodiacetate (yield: 98.8%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:5]=3[N:4]([CH3:20])[C:3]2=[O:21])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc2c(c1)N(C)C(=O)C(N)N=C2c1ccccc1
Reactant: COc1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccc(C)cc3N(C)C2=O)c1
Reaction time: 0.33 h

Procedure:
Equimolar amounts of 3-(R,S)-amino-1,3-dihydro-1,8-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 3-methoxyphenylisocyanate, and triethylamine were mixed in THF at 0° C. and stirred 20 minutes. Removal of THF in vacuo and crystallization from MeOH gave the title compound: m.p. 184°-188° C.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[C:8](Cl)[S:7][N:6]=1)[CH:2]=[CH2:3].NC(N)=[S:13].O1CCCC1>O>[CH2:1]([S:4][C:5]1[N:9]=[C:8]([SH:13])[S:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCSc1nsc(Cl)n1
Reactant: NC(N)=S
Solvent: C1CCOC1
Solvent: O
Product: C=CCSc1nsc(S)n1
Reaction time: 8.5 h
Yield: 57.4 %

Procedure:
A mixture of 3-allylthio-5-chloro-1,2,4-thiadiazole (15.0 g), thiourea (5.95 g), tetrahydrofuran (45 ml) and water (15 ml) was gently boiled for 8.5 hours at 65° C. The reaction mixture was post-treated according to conventional manner to give powder of 3-allylthio-1,2,4-thiadiazole-5-thiol (8.5 g), mp. 107° to 108° C.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:16]1[NH:17][N:18]=[N:19][C:20]=1[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.[NH2:29][C:30]([NH2:32])=[O:31].Cl>CCO>[N:16]1[NH:17][N:18]=[N:19][C:20]=1[C:21]1[CH:28]=[CH:27][C:24]([CH:25]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:32][C:30](=[O:31])[NH:29]2)=[CH:23][CH:22]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(-c2nn[nH]n2)cc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2ccc(-c3nn[nH]n3)cc2)N1
Yield: 15 %

Procedure:
A mixture of 1,2-diphenylethanone (150 mg, 0.76 mmol), 4-(2H-tetrazol-5-yl)benzaldehyde (400 mg), urea (230 mg, 3.8 mmol) and conc. HCl (0.5 mL) in EtOH (5 mL) was refluxed under N2 overnight. Solvent was removed in vacuo and purified by prep-HPLC (0.1% TFA as additive) to give Compound 164 (45 mg, yield 15%) as off-white solid. 1H NMR DMSO-d6 400 MHz): δ 8.75-8.68 (m, 1H), 8.00 (d, J=8.0 Hz, 2H), 7.65-7.60 (m, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.28-7.16 (m, 5H), 7.06-6.96 (m, 3H), 6.84-6.78 (m, 2H), 5.28 (s, 1H). MS (ESI): m/z 395.5 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[C:13]([S-:15])#[N:14].[K+].CC(C)=O>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:14]=[C:13]=[S:15])=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)N=C=S

Procedure:
The product of Example 1B (˜60 mmol) and KSCN (5.83 g, 60 mmol) were mixed in anhydrous tetrahydrofuran (25 mL) and anhydrous acetone (40 mL) and stirred at room temperature for 2 hrs. The reaction was diluted with diethyl ether (100 mL), filtered through celite and solvents evaporated in vacuo to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 3.95 (s, 3H), 6.95 (d, 1H), 7.52 (dd, 1H), 7.84 (d, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][NH2:14])[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[NH2:15][C:16]1[C:17]([C:24]([NH:26][C:27](=N)SC)=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1>CC(O)C>[OH:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:13][NH:14]/[C:27](=[N:26]\[C:24]([C:17]3[C:16]([NH2:15])=[N:21][C:20]([NH2:22])=[C:19]([Cl:23])[N:18]=3)=[O:25])/[NH:1]2)=[CH:11][CH:10]=1
Reactant: NC[C@H](N)CCCc1ccc(O)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@@H](CCCc3ccc(O)cc3)N2)nc1Cl
Temperature: 30 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (4-((R)-4,5-Diamino-pentyl)-phenol (intermediate K) (1.5 g, 7.72 mmol) in propan-2-ol (100 ml) at 30° C. is added in one portion 1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) and the reaction is heated at 30° C. for 18 hours followed by 50° C. for a further 18 hours. The reaction mixture is filtered hot and the filtrate solvent is removed in vacuo to afford a yellow foam. The foam is purified by chromatography (SiO2, DCM/MeOH/5% NH3) to afford the title compound; [M+H]+ 390
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:32]2[CH2:37][NH:36][CH2:35][CH2:34][NH:33]2)[CH:28]=[CH:29][C:30]=1[CH3:31].O>CS(C)=O>[CH3:24][C:25]1[CH:26]=[C:27]([CH:32]2[NH:33][CH2:34][CH2:35][N:36]([C:22]3[C:2]([F:1])=[CH:3][C:4]4[N:13]=[CH:12][C:11]5[N:10]([CH3:14])[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=5[C:5]=4[CH:21]=3)[CH2:37]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(C2CNCCN2)cc1C
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(F)cc3c2c1=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2cnc3cc(F)c(N4CCNC(c5ccc(C)c(C)c5)C4)cc3c2c1=O
Temperature: 100 °C
Yield: 42 %

Procedure:
A stirred suspension of 2.5 g of ethyl 8,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 2.6 g of 2-(3,4-dimethylphenyl)piperazine in 45 cm3 of dimethyl sulphoxide was heated at a temperature in the region of 100° C. for about 100 hours. The reaction mixture was treated with 400 cm3 of water and filtered. The residue obtained was chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 5.5 cm, height 45 cm), eluted at an argon pressure of 120 kPa with a mixture of dichloromethane and ethanol (92/8 mixture by volume) and 50 cm3 fractions were collected. Fractions 37 to 80 were combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.61 g of ethyl 9-[3-(3,4-dimethylphenyl)piperazin-1-yl]-8-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of a yellow solid, which melted at 290° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[C:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[N:17]=2)[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:23])([F:25])[F:24])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:37][CH2:38]4)=[CH:29][CH:28]=3)[N:17]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CC1
Reaction time: 16 h
Yield: 162.4 %

Procedure:
A suspension of 10% Pd/C (200 mg), tert-butyl 4-(4-((4-((2-(1-(methoxycarbonyl)cyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A3) (0.302 g, 0.487 mmol) and Et3N (1.0 mL) in DMF (10 mL) was stirred under an atmosphere of hydrogen for 16 hours. The resulting mixture was diluted with EtOAc (60 mL) and filtered through Celite. The filtrate was evaporated under reduced pressure to give the title compound A4 as a yellow oil (494 mg, 99%); 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 8.68 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.33-7.26 (m, 3H), 7.22-7.17 (m, 3H), 4.07 (d, J=11.6 Hz, 2H), 3.49 (s, 3H), 3.15-3.07 (m, 2H), 3.07-3.00 (m, 2H), 2.86-2.75 (m, peaks obscured by solvent), 2.70-2.58 (m, 1H), 1.74 (d, J=11.3 Hz, 2H), 1.58 (d, J=3.4 Hz, 2H), 1.48 (dt, J=12.6, 6.2 Hz, 2H), 1.42 (s, 9H), 1.21 (s, 2H). LCMS-A: rt 7.175 min; m/z 625 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N+:6]([O-])[CH:7]=1.CS([Cl:16])(=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:2]1[C:3]([Cl:16])=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N:6][CH:7]=1
Reactant: [O-][n+]1cc(Br)cc2nc[nH]c21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1c(Br)cnc2[nH]cnc12
Temperature: 73 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
6-Bromo-3H-imidazo[4,5-b]pyridine 4-oxide (1.88 g, 8.82 mmol) in N,N-dimethylformamide (12 mL) was heated to 50° C., mixed with methansulfonyl chloride (8.00 mL, 103 mmol) and stirred at 73° C. for 3 hours. The reaction mixture was cooled with ice and gradually poured into saturated aqueous sodium hydrogen carbonate (75 mL), and the precipitated solid was collected by filtration, washed with water and chloroform and dried under reduced pressure to give the title compound as a dark brown solid (1.07 g, yield 52%).
Reaction SMILES: [CH3:1][C:2]1[S:21][C:5]2[NH:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH2:22]([O:24][C:25](=[O:36])[C:26](=[CH2:35])[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:23]>CCO>[C:28]([NH:27][CH:26]([CH2:35][N:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:4]3[CH:3]=[C:2]([CH3:1])[S:21][C:5]=3[NH:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[N:9]=2)[CH2:12][CH2:13]1)[C:25]([O:24][CH2:22][CH3:23])=[O:36])([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29]
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCNCC1
Solvent: CCO
Product: CCOC(=O)C(CN1CCN(C2=Nc3ccccc3Nc3sc(C)cc32)CC1)NC(=O)OC(C)(C)C

Procedure:
A mixture of 2-methyl-4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, compound D above, (0.14 g, 0.46 mmol, 1 eq) and N-Boc-dehydroalanine ethyl ester (G, 0.1 g, 0.46 mmol, 1 eq) in 4 ml of anhydrous EtOH was refluxed at 60-65° C. overnight. The solvent was evaporated to dryness and the crude product was purified by flash chromatography (eluent—40% EtOAc in Hexanes). Yield—0.15 g (65%)
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29](I)[CH3:30]>CN(C=O)C.O>[CH2:29]([N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][N:9]2[C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1)[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:30]
Reactant: CCI
Reactant: CSc1nccc(-n2ccc3c(NS(C)(=O)=O)cccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1cccc2c1ccn2-c1ccnc(SC)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
N-[1-(2-Methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yl]-methanesulfonamide (0.4 g) in DMF (2 mL) was treated with K2CO3 (0.83 g) followed by EtI (0.2055 g), stirred at RT overnight, diluted with water, the solid filtered, washed with water and dried at 50° C. in vacuo overnight to yield N-ethyl-N-[1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yl]-methane-sulfonamide (0.4 g).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:22][C:23]1[N:24]=[N:25][N:26]([CH2:28][C:29]([O:31]CC)=[O:30])[N:27]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.C(OC(C)C)(C)C>O1CCCC1>[C:3]([NH:22][C:23]1[N:24]=[N:25][N:26]([CH2:28][C:29]([OH:31])=[O:30])[N:27]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cn1nnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: O=C(O)Cn1nnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To an aqueous solution (27 ml) of sodium hydroxide (2.1 g) were added ethyl 2-(5-tritylamino-2H-tetrazol-2-yl)acetate (14.2 g), methanol (50 ml) and tetrahydrofuran (100 ml), and the mixture was stirred at 40° C. for 2 hours. After the organic solvent was removed by evaporation, to the residue were added water (50 ml) and ethyl acetate (50 ml), followed by separating out the aqueous layer. Thereto was added ethyl acetate (100 ml) and then adjusted to pH 1.5 with 10% hydrochloric acid. The aqueous solution was washed with an aqueous sodium chloride (50 ml) and dried over magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether to obtain 2-(5-tritylamino-2H-tetrazol-2-yl)acetic acid (9.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[CH3:9].Cl[CH:18](Cl)[C:19]([OH:21])=[O:20].[C:23](=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)(C)C.CO>[CH3:9][CH:8]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH:18]([C:19]([O:21][CH3:23])=[O:20])[O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: O=C(O)C(Cl)Cl
Reactant: O=C([O-])[O-]
Reactant: CC(c1ccccc1O)c1ccccc1O
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)O
Product: COC(=O)C1Oc2ccccc2C(C)c2ccccc2O1

Procedure:
1,1-Bis(2-hydroxyphenyl)ethane was treated with dichloroacetic acid, potassium carbonate, and potassium iodide in isopropyl alcohol as in Example 3 and the product obtained was esterified with methanol as in Example 4 to obtain 1.71 g of the title compound as a mixture of cis and trans isomers. A portion of this was recrystallized from ether to obtain a pure sample of the cis isomer of the title compound as a white solid melting at 146°-147° C. The geometry was determined by proton NMR spectroscopy.
Reaction SMILES: C([O:4][CH:5]=[CH2:6])(=O)C.[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].ON1[C:24]2C=CC=C[C:23]=2N=N1.CCN=C=NCCCN(C)C>O.C(Cl)(Cl)Cl>[C:14]([O:13][C:12](=[O:18])[NH:11][CH2:10][CH2:9][CH2:8][NH:7][C:5](=[O:6])[CH2:4][CH:23]=[CH2:24])([CH3:15])([CH3:17])[CH3:16]
Reactant: C=COC(C)=O
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCC(=O)NCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a chloroform solution (58 mL) of vinyl acetate (500 mg, 5.81 mmol) were added tert-butyl N-(3-aminopropyl)carbamate (2.02 g, 11.6 mmol), 1-hydroxybenzotriazole (0.86 g, 6.39 mmol) and WSC (1.56 g, 8.13 mmol), and the mixture was stirred overnight at room temperature. To the reaction solution was added water and the resulting mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1, ethyl acetate) to obtain the title compound (1.32 g, 94%) as a colorless powder.
Reaction SMILES: Cl.[CH3:2][NH2:3].O1CCCC1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][S:15][CH2:16][CH2:17][NH:18][C:19]([NH:25][CH2:26][CH:27]([OH:35])[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)=[N:20][S:21]([CH3:24])(=[O:23])=[O:22].[OH-].[Na+].[CH2:38]=O>O>[OH:35][CH:27]([C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[CH2:26][NH:25][C:19]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[N:18][CH2:17][CH2:16][S:15][CH2:14][C:10]1[O:9][C:13]([CH2:2][NH:3][CH3:38])=[CH:12][CH:11]=1
Reactant: C=O
Reactant: CN
Reactant: CS(=O)(=O)N=C(NCCSCc1ccco1)NCC(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNCc1ccc(CSCCN=C(NCC(O)c2ccc(O)cc2)NS(C)(=O)=O)o1
Reaction time: 5 h
Yield: 40 %

Procedure:
240 mg of methylamine hydrochloride was dissolved in a 0.27 ml of 37% (w/w) aqueous formalin solution. Thereto was added, at room temperature, 2.5 ml of a tetrahydrofuran solution containing 500 mg of N-[2-[(2-furyl)methylthio]ethyl]-N'-[2-hydroxy-2(4-hydroxyphenyl)ethyl]-N"-methanesulfonylguanidine. The mixture was stirred at the same temperature for 5 hours. The reaction mixture was introduced into 30 ml of water. The resulting mixture was adjusted to pH 9.5 with a 1N aqueous sodium hydroxide solution and extracted with two 50-ml portions of a 1:1 mixture of ethyl acetate and tetrahydrofuran. The extracts were combined and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant:chloroform:methanol:aqueous ammonia solution=85:15:1) to obtain 220 mg (yield: 40%) of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-N'-methanesulfonyl-N"-[2-[[5-(methylamino)methyl-2-furyl]methylthio]ethyl]guanidine.