Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10](Br)([CH3:12])[CH3:11])=[O:9])=[CH:4][CH:3]=1.[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:14]1([C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])([CH3:12])[CH3:11])[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(Br)C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C(=O)c1ccc(Cl)cc1)n1cncn1
Yield: 25.7 %

Procedure:
80 g (0.31 mole) of 2-bromo-prop-2-yl 4-chlorophenyl ketone, 26.9 g (0.39 mole) of 1,2,4-triazole and 53.8 g (0.39 mole) of potassium carbonate are heated under reflux in 350 ml of acetone for 6 hours. The mixture is allowed to cool and is filtered and the filtrate is concentrated in vacuo. The residue is taken up in methylene chloride and the mixture is washed with water, dried over sodium sulphate and concentrated in vacuo. The residue is recrystallised from diisopropyl ether. 19.9 g (25.7% of theory) of 4-chlorophenyl 2-(1,2,4-triazol-1-yl)-prop-2-yl ketone of melting point 111° C. are obtained. ##STR19##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][OH:22]>>[CH3:21][O:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: CO
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(OC)c2c1

Procedure:
Similar procedure as described in example 10 was used, starting from Methanol, (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-Methoxy-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 285(MH+).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:14](=[O:19])[NH:15]2
Reactant: C#CCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCC#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 4-pentynoic acid methyl ester (75.7 mg, 0.68 5 mmol) (see Example 8, supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (31.2 mg) and Cul (5.0 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 7 h to yield (Z)-5-[2,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 86 mg, 90%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16].CO.O>CN(C=O)C>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:16][C:15]2[C:14]([F:13])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1c(F)cccc1F
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(Cl)c(C#N)c(Nc2c(F)cccc2F)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50° C. for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH/H2O (20 mL, 1:1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile as a white solid (2.82 g, 90%). LC-MS m/z 313 (M+H)+; 1H-NMR (CDCl3) δ 2.33 (s, 3H), 6.94 (s, 1H), 7.04 (m, 2H), 7.35 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)CCCC(C)(C)N1.C([Li])CCC.Cl[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39]>O1CCCC1.CCCCCC.O>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([O:38][CH3:39])[CH:32]=2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCCN1Cc1ccccc1
Reactant: COc1ccccc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C2CCCCN(Cc3ccccc3)C2=O)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-Benzylhexahydro-2H-azepin-2-one (10.2 g) in tetrahydrofuran (100 ml) was added dropwise to a stirred, cooled solution of lithium-2,2,6,6-tetramethylpiperidide [prepared by the addition of 2,2,6,6-tetramethylpiperidine (8.5 g) to butyl lithium (0.05 mole) in hexane (32 ml)] under nitrogen. When the addition was completed a further portion of butyl lithium (0.05 mole) in hexane (32 ml) was added. The solution was cooled to 0° C. and o-chloroanisole (6.2 ml) added dropwise. After stirring at room temperature for four hours the reaction was decomposed with water and the solvents removed under reduced pressure. The resulting oil was partitioned between 5 M hydrochloric acid and toluene. After drying (MgSO4) the toluene was removed to leave an oil which was distilled affording 5.02 g b.p. 180°-220° C. at 0.2 mm. The oil was crystallised from methanol, affording 3.15 g m.p. 120°-122° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[N:4]1)[CH3:2].[NH:17]1[CH2:23][CH2:22][CH2:21][CH:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19][CH2:18]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:18]2[N:17]=[CH:23][C:6]3[CH:5]=[N:4][N:3]([C:1]4[N:24]=[C:20]([N:17]5[CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19][CH2:18]5)[CH:21]=[CH:22][CH:2]=4)[C:7]=3[CH:19]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)NC1CCCNCC1
Product: CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCC(N)CC3)n2)cn1
Yield: 12 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and tert-butyl azepan-4-ylcarbamate, 140 was obtained as an off-white solid (16.2 mg, 12%) over 2 steps. 1H NMR (400 MHz, DMSO) δ 9.15-9.11 (s, 1H), 8.70-8.65 (d, J=9.8 Hz, 1H), 8.54-8.47 (d, J=8.1 Hz, 1H), 8.28-8.25 (d, J=7.4 Hz, 1H), 7.95-7.87 (s, 1H), 7.73-7.66 (dd, J=10.5, 5.7 Hz, 1H), 7.18-7.12 (d, J=7.7 Hz, 1H), 6.60-6.54 (t, J=6.6 Hz, 1H), 4.25-4.18 (q, J=7.3 Hz, 2H), 3.95-3.86 (s, 1H), 3.85-3.77 (m, 1H), 3.75-3.58 (ddd, J=20.2, 14.0, 9.4 Hz, 2H), 2.94-2.85 (dd, J=12.2, 6.3 Hz, 1H), 2.07-1.96 (m, 2H), 1.83-1.74 (m, 1H), 1.74-1.66 (d, J=14.4 Hz, 1H), 1.65-1.56 (ddd, J=13.0, 9.1, 4.5 Hz, 1H), 1.46-1.41 (t, J=7.3 Hz, 3H), 1.42-1.34 (dd, J=14.2, 4.0 Hz, 1H); MS (ESI) m/z: 403.2 [M+H]+
Reaction SMILES: [CH3:1][NH:2][C:3]1([CH3:21])[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[C:7]([O:13]CC3C=CC=CC=3)[CH:6]=[CH:5][C:4]1=2.[ClH:22].[H][H]>C(O)C.CC(O)C.[Pd]>[ClH:22].[CH3:21][C:3]1([NH:2][CH3:1])[CH2:12][CH2:11][CH2:10][C:9]2[NH:8][C:7](=[O:13])[CH:6]=[CH:5][C:4]1=2
Reactant: CNC1(C)CCCc2nc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: CNC1(C)CCCc2[nH]c(=O)ccc21
Yield: 25 %

Procedure:
5,6,7,8-Tetrahydro-N,5-dimethyl-2-(phenylmethoxy)-5-quinolinamine (6.3 g) in ethanol (500 ml) was acidified to ca pH2 with a solution of hydrochloric acid in 2-propanol. 10% Palladium-on-carbon (315 mg) was added and the mixture was shaken on Parr hydrogenation apparatus, starting at 55 psi of hydrogen, until hydrogen uptake ceased. The catalyst was collected and the filtrate was neutralized with 4-polyvinylpyridine. The solution was concentrated in vacuo to a volume of about 75 ml and diethyl ether was added. The precipitate was collected and recrystallized first from methanol and then from water/2-propanol to afford 1.3 g (25%) of product, mp 190°-195° C. (dec).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:12]#[N:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:1]1([CH:7]([NH:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[CH2:12][NH2:13])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(Nc1cccc(-c2ccccc2)c1C#N)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(Nc1cccc(-c2ccccc2)c1CN)c1ccccc1
Temperature: 25 °C

Procedure:
The product of example 3a above, (+/−)-2-[(1-phenyl)ethylamino]-6-phenybenzonitrile, (0.13 g, 0.43 mmol) was dissolved in dry tetrahydrofuran (10 mL) and stirred under argon at room temperature. Lithium aluminum hydride (0.172 g, 4.3 mmol) was added and the mixture heated to reflux under argon for 20 hours. The reaction mixture was cooled to room temperature and anhydrous sodium sulfate was added followed by the addition of a freshly prepared saturated solution of anhydrous sodium sulfate. The solvent was evaporated and the residue triturated with ethyl acetate, filtered and evaporated. Flash chromatography on silica gel eluted with 0-3% methanol in methylene chloride followed by recrystallization from ethyl acetate/hexane gave the title compound as a white crystalline solid. ES (+) MS n/e=303 (MH+)
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([N+:19]([O-])=O)=[CH:17][CH:18]=2)[CH:9]=[CH:8][N:7]=1)=[O:4].[NH4+].[Cl-]>CO.[Zn]>[NH2:19][C:16]1[N:15]=[CH:14][C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:22])[CH:11]=2)=[CH:18][CH:17]=1
Reactant: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CN(C)C(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A solution of 1,1-dimethyl-3-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea (0.631 g, 2.081 mmol) in MeOH (20 mL) was treated with NH4Cl (3.34 g, 62.4 mmol) followed by zinc dust (1.361 g, 20.81 mmol) and stirred at RT overnight. The solids were removed via filtration, washed with THF and the filtrate concentrated to dryness to afford 3-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-1,1-dimethylurea (560 mg, 98%). MS (ESI) m/z: 274.1 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[C:10]([NH2:11])=[CH:9][S:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[CH3:2][O:3][C:4]([C:6]1[C:10]([NH:11][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][O:22][C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[Cl:19])=[CH:9][S:8][CH:7]=1)=[O:5]
Reactant: O=C(Cl)CCCOc1ccccc1Cl
Reactant: COC(=O)c1cscc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cscc1NC(=O)CCCOc1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To 4-amino-thiophene-3-carboxylic acid methyl ester hydrochloride (199 mg, 0.994 mmol) in dichloromethane (1.9 mL) and triethylamine (0.29 mL, 2.08 mmol), was slowly added a crude solution of 4-(2-chloro-phenoxy)-butyryl chloride (271 mg, approximately 1.16 mmol) in dichloromethane (1.9 mL). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then further diluted with dichloromethane (50 mL) and washed with water. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried with sodium sulfate, and concentrated in vacuo. The residue was then purified by column chromatography (SiO2, Heptane/EtOAc: 0-80%) to yield the title compound as a white solid (281 mg, 80%).
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH3:41])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[O:25])[CH:15]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4]>C(Cl)Cl.CO>[CH3:1][C:2]([CH3:42])([CH3:41])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CN1CCN(C(=O)Cn2cc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c3ccccc32)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(C(=O)Cn2cc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c3ccccc32)CC1
Yield: 67 %

Procedure:
2,2-Dimethyl-1-(2-{1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-indol-3-yl}-5H-pyrrolo[2,3-b]pyrazin-7-yl)-propan-1-one was prepared following the same procedure but using 2,2-dimethyl-1-[2-{1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-indol-3-yl}-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as starting material. The product was isolated in 67% yield by SiO2 chromatography (DCM/MeOH 0-10% MeOH).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[C:5]([CH3:17])([CH3:16])[C:4](=[O:18])[C:3]=1[C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20]>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:14])([F:15])[F:13])[C:5]([CH3:17])([CH3:16])[C:4](=[O:18])[C:3]=1[C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2c(C(F)(F)F)cccc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2c(C(F)(F)F)cccc21
Yield: 6.1 %

Procedure:
1,1-Dimethylethyl N-((4-hydroxy-1,1-dimethyl-2-oxo-5-(trifluoromethyl)-naphthalen-3-yl)carbonyl)glycinate (30 mg, 73 μmol) was stirred in TFA (5 mL) for 15 minutes. The TFA was then removed under vacuum. The residue was purified by preparatory scale TLC (5% MeOH/DCM eluent) to give the desired product as a light yellow oil (1.6 mg). MS (m/z)=358.4 (M+H)+. Calculated for C16H14F3NO5 357.08.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH:40]=[C:41]([CH2:45][NH2:46])[CH:42]=[CH:43][CH:44]=2)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:46][CH2:45][C:41]1[CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:44]=[CH:43][CH:42]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cccc(CN)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN)c4)cc23)CC1
Temperature: 160 °C
Yield: 8.5 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30.0 mg, 0.072 mmol), Cs2CO3 (95 mg, 0.290 mmol) and 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (82 mg, 0.350 mmol) in dioxane/H2O (2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (7.5 mg, 0.0072 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, concentrated, and purified by reverse phase HPLC method A (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (2.7 mg, 8.5%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([OH:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(C(C)C)C(C)C)C.O>CC(C)=O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:20])=[C:15]([O:18][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: -20 °C
Yield: 90 %

Procedure:
Benzhydryl 7β-[(phenylacetyl)amino]-3-hydroxy-3-cephem-4-carboxylate (500 g, 1 mol) was dissolved in acetone (2 L) and methanesulfonyl chloride (86 mL, 1.1 mol) was added dropwise over 10 min with stirring at −20° C. Then, ethyldiisopropylamine (183 mL, 1.05 mol) was added dropwise over 30 min and the mixture was stirred at −20° C. for 40 min. The reaction mixture was poured into iced water (8 L) and the precipitate was collected by filtration. The precipitate was then washed with water (2 L) and ethyl acetate (300 mL), and dried under reduced pressure to give the title compound (523 g, 0.90 mol). yield: 90%.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[N:15]1([CH2:21][CH2:22][N:23]([CH2:35][CH2:36][CH3:37])[CH:24]2[CH2:33][CH2:32][C:31]3[C:30]([OH:34])=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:25]2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[OH:34][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[CH2:32][CH2:33][CH:24]([N:23]([CH2:35][CH2:36][CH3:37])[CH2:22][CH2:21][N:15]1[CH2:20][CH2:19][N:18]([CH2:3][C:4]3[CH:13]=[CH:12][C:11]([OH:14])=[C:10]4[C:5]=3[CH:6]=[CH:7][CH:8]=[N:9]4)[CH2:17][CH2:16]1)[CH2:25]2
Reactant: Oc1ccc(CCl)c2cccnc12
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Agent: Cl
Product: CCCN(CCN1CCN(Cc2ccc(O)c3ncccc23)CC1)C1CCc2c(O)cccc2C1
Yield: 77.5 %

Procedure:
This compound was prepared following the procedure H in which compound 11 (0.18 g, 0.8 mmol) and 9b (0.23 g, 0.72 mmol) were used to afford 12b as yellow solid (0.265 g, 59%). 1H NMR of salt (400 MHz, DMSO-d6) δ ppm 0.84-0.87 (t, 3H, J=6 Hz), 1.79-1.81 (bs, 4H), 2.298 (bs, 1H), 2.476-2.48 (m, 2H), 2.74 (s, 2H), 2.96-3.02 (t, 1H, J=12 Hz), 3.122 (bs, 3H), 3.34-3.65 (m, 12H), 6.50-6.52 (d, 1H, J=8 Hz), 6.55-6.57 (d, 1H, J=8 Hz), 6.93-6.96 (t, 1H, J=6 Hz), 7.06-7.08 (d, 1H, J=8 Hz), 7.32-7.34 (d, 1H, J=8 Hz), 7.44-7.46 (m, 1H), 8.66-8.68 (d, 1H, J=8 Hz), 8.77-8.78 (d, 1H, J=4 Hz). The hydrochloride salt mp 252-255° C. Analysis calculated for (C29H43N4O4.5, 4HCl) C, H, N.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:41])[N:19](C(OC(C)(C)C)=O)[CH2:20][C:21]=2[C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)=[CH:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[C:22]1([C:21]2[CH2:20][NH:19][C:18](=[O:41])[C:17]=2[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][CH:9]=2)[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cn3c4c(cccc24)CCC3)=C(c2cn(C(=O)OC(C)(C)C)c3ccccc23)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NCC(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
A mixture of 3-[1-tert-butoxycarbonyl-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-indole-1-carboxylic acid tert-butyl ester (408 mg, 738 μmol) and 4M HCl in dioxane (15 mL) was shaken at room temperature for 16 h. The solvent was removed and the residue partitioned between EtOAc and 2N NaOH. The organics were concentrated and the residue purified by flash column chromatography (SiO2, DCM/MeOH). The solid obtained was recrystallised from DCM to afford 4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-1,5-dihydro-pyrrol-2-one as a pale yellow solid (159 mg, 61%). M.p.=260-262° C.; 1H NMR (400 MHz, DMSO-d6) δ: 11.22 (s, 1H), 8.16 (s, 1H), 7.44-7.39 (m, 2H), 7.31 (s, 1H), 7.05-6.95 (m, 3H), 6.82-6.74 (m, 3H), 4.51 (s, 2H), 4.00 (t, J=5.6 Hz, 2H), 2.86 (t, J=6.0 Hz, 2H), 2.05 (t, J=5.2 Hz, 2H). LCMS: m/e 354.12 [M+H].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].II>C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][S:7][C:4]2[S:3][C:2]([NH2:1])=[N:6][N:5]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nnc(SSc2nnc(N)s2)s1

Procedure:
A solution prepared from 10.0 g 2-amino-1,3,4-thiadiazole-5-thiol, 81 g ethanol and 7.78 g 40% aqueous NaOH was mixed with a solution of 9.48 g iodine in 75 g of ethanol. The resulting mixture was filtered, and the collected product was washed with ethanol and dried under vacuum at 70° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[N:3]1[S:25]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=[O:27])=[O:26].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[N:3]1[S:25]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=[O:27])=[O:26]
Reactant: CC1C=Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2N1S(=O)(=O)c1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCc2c(N3CCNCC3)cccc2N1S(=O)(=O)c1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
The compound prepared in example 8 (260 mg, 0.62 mmol) was dissolved in a mixture of 1 mL TFA and 4 mL CH2Cl2 and stirred for 30 min. The solvent was evaporated and the crude product was purified by a short silica gel column (using CH2Cl2-MeOH 98:2 as eluent). Yield: 180 mg (85.6%) Rf=0.38 (CH2Cl2-MeOH 9:1).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][N:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)N1CCN(CCc2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(CCN2CCNCC2)cc1
Yield: 59.5 %

Procedure:
As in the foregoing Example, 48.6 g of the carbamate is hydrolyzed with 50 g potassium hydroxide in 50 ml ethanol at 120° C. Processing gives 21.5 g (60%) 1-[2-(4-fluorophenyl)ethyl]piperazine with a b.p. of 142° C./3 Torr. It may be transformed into a dimaleate crystallizing from 95% ethanol as a hemihydrate and melting at 164.5°-166.5° C.