Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:14][CH2:13][NH:12][C:11]1=[S:15].[I:16]I.[I].[K]>CO.O>[IH:16].[NH:12]1[CH2:13][CH2:14][N:10]=[C:11]1[S:15][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: S=C1NCCN1
Reactant: II
Agent: [I]
Agent: [K]
Solvent: CO
Solvent: O
Product: I
Product: c1ccc2c(SC3=NCCN3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 11.7 g indole in 100 ml methanol and 10.2 g 2-imidazolidinethione in 150 ml methanol is added to a well-stirred solution of 25.4 g iodine and 50 g potassium iodine in 100 ml water. The mixture is stirred for 2 hours at room temperature. The clear solution is concentrated in vacuo to one third of the original volume and cooled. The solid which separates is filtered off, dried and recrystallised from alcohol-ether to give 3-(2-imidazolin-2-ylthio)-indole hydriodide of the formula ##STR11## melting at 210°-211°.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[C:6](Cl)=[N:7]2.[CH3:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21].[O:24]1CCOCC1>>[CH3:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH:21][C:6]1[C:5]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:4]=2[C:3]2[C:2](=[O:24])[NH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CC(C)(C)CN
Reactant: C1COCCO1
Reactant: Fc1ccc2c(Cl)nc3ccnc(Cl)c3c2c1
Product: CC(C)(C)CNc1nc2cc[nH]c(=O)c2c2cc(F)ccc12
Temperature: 100 °C

Procedure:
To a solution of 1,6-dichloro-9-fluorobenzo[c]-1,6-naphthyridine (20 mg, 0.075 mmol) in dioxane (1.5 mL) was added 2,2-dimethylpropan-1-amine (39 mg, 0.45 mmol) and heated in a microwave reactor at 100° C. for 30 to 50 min. The solution was concentrated and converted to 6-[(2,2-dimethylpropyl)amino]-9-fluorobenzo[c]-1,6-naphthyridin-1(2H)-one in a similar manner exemplified in the synthesis of 9-bromo-6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}benzo[c]-1,6-naphthyridin-1(2H)-one (Method A, Step 2). 1H NMR (600 MHz, CD3OD) δ 9.65 (dd, 1H), 8.60 (dd, 1H), 7.60 (d, 1H), 7.58 (m, 1H), 6.95 (d, 1H), 3.70 (s, 2H), 1.10 (s, 9H). LRMS (ESI) calc'd for (C17H19FN3O) [M+H]+, 300.15; found 300.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Br)[C:10]=1/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]([Si:48]([CH3:57])([CH3:56])[O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]=O)([CH3:47])([CH3:46])[CH3:45]>C(#N)C.O1C(CC)C1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH:54][CH2:53][CH2:52][CH2:51][CH2:50][O:49][Si:48]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:57])[CH3:56])[C:10]=1/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCC=O
Reactant: CCOC(=O)/C=C/c1c(CBr)cccc1OCCCC(=O)OCC
Agent: CCC1CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)/C=C/c1c(C=CCCCCO[Si](C)(C)C(C)(C)C)cccc1OCCCC(=O)OCC
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A solution of 4-[3-bromomethyl-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (2.0 mmol, 798 mg) and triphenylphosphine (2.2 mmol, 577 mg) in acetonitrile (12 mL) was heated to reflux for 1 h under nitrogen atmosphere. Then, it was cooled to room temperature and a solution of 5-(tert-butyl-dimethyl-silanyloxy)-pentanal (2.8 mmol, 606 mg) in 1,2-epoxybutane (22 mL) was added at room temperature and the mixture was again heated to reflux for 15 h. During this period, the mixture first turned to a brick red color and at the end of the reaction it had become a pale yellow solution. Then, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was dissolved in a solution of ethyl acetate and hexanes (1:3, 150 mL) and the resulting cloudy solution was washed with a mixture of methanol and water (2:1, 225 mL). The aqueous layer was extracted one more time with ethyl acetate and hexanes (1:3, 50 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave light brown oil. The crude mixture was purified by using a Biotage™ (40 L) column chromatograph eluting with 5 and 15% ethyl acetate in hexanes to obtain the desired 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hex-1-enyl]-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (760 mg, 74%) as a colorless oil: ES(+)-HRMS m/e calculated for C29H46O6Si (M+Na)+ 541.2956. found 541.2953.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23].[CH:24]([NH2:27])([CH3:26])[CH3:25]>C1C=CC=CC=1>[CH:24]([NH:27][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNC(C)C)C1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3.2 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester in 30 ml. of benzene containing 650 mg. of isopropylamine is allowed to stir at room temperature for 48 hrs. The reaction solution is concentrated to give 4 g. of a yellow foam which could not be induced to crystallize.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1.[C:33]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH2:40])=[O:39])#[CH:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:16]2[CH:31]=[CH:32][C:13]([NH:12][C:4]3[N:3]=[C:2]([C:34]#[C:33][C:35]4[CH:43]=[CH:42][CH:41]=[C:37]([C:38](=[O:39])[NH2:40])[CH:36]=4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=3)=[CH:14][CH:15]=2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: C#Cc1cccc(C(N)=O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4cccc(C(N)=O)c4)n3)cc2)CC1
Temperature: 120 °C
Yield: 29 %

Procedure:
tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I94) (0.30 g, 0.64 mmol), 3-ethynylbenzamide (I144) (102 mg, 0.70 mmol), copper(I) iodide (12 mg, 10 mol %), triphenylphosphine (17 mg, 10 mol %), bis(triphenylphosphine)palladium(II) chloride (22 mg, 5 mol %), DMF (3 mL) and triethylamine (0.443 mL, 3.18 mmol) were loaded into a microwave tube and degassed with nitrogen for five minutes. The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes then cooled to room temperature. The cooled mixture was added to 5% aqueous potassium carbonate (I50 mL) and the resulting mixture extracted with ethyl acetate (3×150 mL). The combined ethyl acetate phases were washed with water (200 mL), brine (200 mL), dried then evaporated. The residue was chromatographed (Biotage Isolera: 12 g silica cartridge, 20-100% ethyl acetate/petroleum benzine 40-60° C. then 0-10% methanol/ethyl acetate) to give the title compound (I145) (107 mg, 29% yield) as a yellow solid; 1H NMR (400 MHz, d5-DMSO) δ 10.46 (s, 1H), 8.84 (s, 1H), 8.17 (s, 1H), 8.09 (t, J=1.7 Hz, 1H), 8.04 (dt, J=7.9, 1.4 Hz, 1H), 7.77 (dt, J=7.8, 1.3 Hz, 1H), 7.71-7.66 (m, 2H), 7.66-7.52 (m), 7.27 (d, J=8.6 Hz, 2H), 3.44 (s, 2H), 2.33-2.26 (m, 4H), 1.38 (s, 9H). LCMS Method C: rt 5.06 min; m/z 581.1 [M+H]+, 525.1 [M−tBu+2H]+; m/z 579.2 [M−H]−.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:18]S(C)(=O)=C>>[O:3]1[C:2]([CH3:18])([CH2:4][CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:1]1
Reactant: CC(=O)CC(c1ccccc1)c1ccccc1
Reactant: C=S(C)(C)=O
Product: CC1(CC(c2ccccc2)c2ccccc2)CO1

Procedure:
The 1,2-epoxy-4,4-diarylbutane starting materials can alternatively be prepared by reaction of dimethylsulfonium methylide or dimethyloxosulfonium methylide with an appropriate diarylalkyl aldehyde or a diarylalkyl ketone. For example, reaction of an aldehyde such as 3,3-diphenylpropanal with either dimethylsulfonium methylide or dimethyloxosulfonium methylide in approximately equimolar amounts provides 1,2-epoxy-4,4-diphenylbutane. Similarly, reaction of a diarylalkyl ketone such as methyl-(2,2-diphenylethyl) ketone with either dimethylsulfonium methylide or dimethyloxosulfonium methylide provides 1,2-epoxy-4,4-diphenyl-2-methylbutane. Such reactions typically are carried out in a solvent such as dimethyl sulfoxide or tetrahydrofuran, and normally at a reduced temperature of about 0° C. Dimethylsulfonium methylide is prepared by reaction of trimethylsulfonium iodide with methylsulfinylcarbanion, while dimethyloxosulfonium methylide is prepared by reaction of trimethyloxosulfonium iodide with sodium hydride. Such reactions are more fully discussed by Corey et al., J. Am. Chem. Soc., 84, 867(1962) and J. Am. Chem. Soc., 84, 3782 (1962).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][NH:8][C:7]2=O.O=P(Cl)(Cl)[Cl:15].CN(C)C1C=CC=CC=1.CCCCCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[C:7]2[Cl:15]
Reactant: Cc1cccc2c(=O)[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Cc1cccc2c(Cl)ncnc12

Procedure:
4 g of 8-methyl 4-quinazolinone, 5 ml POCl3 and 5 ml dimethyl aniline in 40 ml toluene were refluxed 3.5 hours. Workup and trituration with hexane gave 2.6 g of 8-methyl 4 chloro quinazoline, mp-122° C. NMR CDCl3 δ 9.07 (1H, S), 8.12 (1H, d, J=7.7 Hz), 7.8 (1H, d, J=6.0 Hz), 7.60 (1H, t), 2.78 (3H, S).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Mg].II.[C:8]1([CH3:16])[CH:13]=[CH:12][C:11]([C:14]#N)=[CH:10][CH:9]=1.S(=O)(=O)(O)[OH:18]>CCOCC>[CH3:16][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1
Reactant: CC(C)Br
Reactant: Cc1ccc(C#N)cc1
Reactant: O=S(=O)(O)O
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: Cc1ccc(C(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
24.6 g of 2-bromopropane was added to a mixture of 4.8 g of magnesium, a few crystals of iodine, and 200 ml of ether. To the resulting Grignard reagent was added a solution of 23.4 g of p-tolunitrile in ether, over a 15-minute period at about 30°. The mixture was stirred at room temperature for 32 hours and refluxed for 3 days, then treated with dilute sulfuric acid, cooled and extracted with ether. The ether solution was dried (MgSO4) and stripped of solvent. The resulting liquid product was cooled, unreacted starting material was decanted. The residue was chromatographed (silica gel, methylene chloride) to give 1-(4-methylphenyl)-2-methyl-1-propanone (5A).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3C=CC=CC=3)=[CH:14][CH:13]=2)=[N:10][C:9]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:8][C:3]=1[C:4](OC)=[O:5].N([O-])=O.[Na+].[N-:38]=[N+]=[N-].[Na+].C([O:44][CH2:45]C)C>FC(F)(F)C(O)=O>[CH3:45][O:44][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]2[C:11]3[N:10]=[C:9]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH:8]=[C:3]([C:4]([NH2:38])=[O:5])[C:2]=3[NH:1][C:13]=2[CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOCC
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OCc3ccccc3)cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(OC)cc3)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-amino-2-(4-(benzyloxy)phenyl)-6-(4-methoxyphenyl)isonicotinate (556 mg, 1.262 mmol) was dissolved in trifluoroacetic acid (6 mL) and the yellow solution cooled in an ice bath. Solid sodium nitrite (174 mg, 2.52 mmol) was added with stirring to give a dark red mixture. After 30 min, solid sodium azide (821 mg, 12.6 mmol) was added followed by diethyl ether (6 mL). The light red mixture was stirred in the ice bath for 30 min. The reaction was concentrated on the rotary evaporator and was then partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed. Radial silica gel chromatography (step gradient elution with hexane containing 0 to 20% EtOAc) afforded the two major products as oils:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([OH:16])=O)[CH3:3].C(N1C=CN=C1)([N:19]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([NH2:19])=[O:16])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(C(N)=O)oc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A suspension of 3-(1-methylethoxy)-2-benzofurancarboxylic acid (200 mg, 0.91 mmol) and 1,1'-carbonyldiimidazole (191 mg, 1.18 mmol) in 5 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and aqueous ammonium hydroxide (3 mL) is added and the reaction mixture is stirred at room temperature for 2 hours. The reaction is diluted with ethyl acetate and washed with 1N HCl, saturated aqueous NaHCO3, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:1) provides 3-(1-methylethoxy)-2-benzofurancarboxamide in 77% yield; mp=82°-83° C.
Reaction SMILES: [C:1]([C:5]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[C:14]([Cl:22])[C:6]=1[N:7](C(=O)C)C(=O)C)([O:3]C)=[O:2].[OH-].[Na+].C>C(O)(=O)C>[Cl:22][C:14]1[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:5]([C:1]([OH:3])=[O:2])[C:6]=1[NH2:7]
Reactant: COC(=O)c1c(OC)c(OC)cc(Cl)c1N(C(C)=O)C(C)=O
Agent: C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(Cl)c(N)c(C(=O)O)c1OC
Yield: 2.7 %

Procedure:
A mixture of 2,4 g (97.3 mmol) of 2-carbomethoxy-6-chloro-N,N-diacetyl-3,4-dimethoxyaniline and 20 mL of 2N sodium hydroxide was refluxed 3.5 hours. The solution was treated with Darco and neutralized with 5 mL of glacial acetic acid. Upon cooling, the product crystallized and was collected by filtration to yield 0.6 g (36%) of a fluffy yellow solid, mp 140°-142° C. NMR (CDCl3) δ 3.82 (s, 3H, OCH3), 4.03 (s, 3H, OCH3). 7.15 (s, 1H, ArH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(N(CC)CC)C.[OH-].[Na+]>N1C=CC=CC=1>[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:6]([C:5]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:7]
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Reactant: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)c2nccn2C)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 16.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 80 ml of pyridine is added dropwise to a solution of 2.68 g of 1-methylimidazole and 6.6 g of triethylamine in 80 ml of pyridine, whereupon the mixture is stirred at 60° for 3 hours. After treatment with 1.70 ml of 3N sodium hydroxide solution the mixture is stirred for an additional 1 hour and subsequently poured into ice-water. The separated grey crystals are filtered under suction and taken up in ethyl acetate, whereupon the organic phase is dried over magnesium sulfate and the solvent is distilled. After recrystallization from ethyl acetate/hexane there is obtained 3,4-dimethoxy-5-nitrophenyl (1-methylimidazol-2-yl) ketone in the form of colorless crystals of m.p. 144°-145°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:33])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccc(C(=O)OC)cc3)nc2s1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5]Br.[CH3:11][C:12]([CH3:14])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][C:12]([CH3:14])([OH:13])[CH3:11])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CC(C)=O
Reactant: Fc1ccc(CBr)cc1F
Product: CC(C)(O)Cc1ccc(F)c(F)c1

Procedure:
From 23.0 g (111 mmol) of 3,4-difluorobenzyl bromide a Grignard is prepared, which is then reacted with 11.6 mL (158 mmol) of acetone. Slightly yellow oil. Yield: 9.7 g (47%); Rf value: 0.55 (ethyl acetate-petroleum ether (1:3)).
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](C(O)=O)[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[C:47](=[O:50])(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:47]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:50])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: Nc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-benzyl-3-oxo-4-(3-carboxyphenyl)-3,4-dihydropyrido[2,3-b]pyrazine (186 mg) and 1,1′-carbonyldiimidazole (130 mg) in tetrahydrofuran (4 ml) was stirred at room temperature for 3 hours. Aniline (0.075 ml) was then added to the mixture and stirring was continued for 24 hours. The reaction mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate, concentrated, and subjected to silica gel column chromatography (chloroform-methanol, 40:1) to afford 2-benzyl-3-oxo-4-(3-anilinocarbonylphenyl)-3,4-dihydropyrido[2,3-b]pyrazine (103 mg) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:26]1([NH:29][CH2:30][CH2:31][NH2:32])[CH2:28][CH2:27]1.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([NH:32][CH2:31][CH2:30][NH:29][CH:26]1[CH2:28][CH2:27]1)=[O:7]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCCNC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCNC1CC1
Yield: 91.7 %

Procedure:
8.06 g (0.04) mole of 2-methoxy-4-amino-5-chlorobenzoic acid and 7.12 g (0.044 mole) of carbonyldiimidazole are suspended in 80 ml of tetrahydrofuran and kept at 30° C. until the end of gas development. The solution of 5 g (0.05 mole) of cyclopropylethylenediamine in 15 ml of tetrahydrofuran is then slowly added, followed by keeping the temperature at 50° C. for 1 hour. After cooling down, the mixture is poured into water, the solid is removed by filtration and crystallized from alcohol, thus obtaining 13 g (91.7%) of 2-methoxy-4-amino-5-chloro-N-(2-(cyclopropylamino)-ethyl)-benzamide, having a melting point of 152°-3° C. Hydrochloride m.p.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.[C:8]([CH2:11][N:12]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:17][CH2:16][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:14][CH2:13]1)([OH:10])=[O:9].[OH-].[K+]>O1CCOCC1.O>[OH:5][CH:3]([C:2]([F:7])([F:6])[F:1])[CH2:4][N:21]1[CH2:22][CH2:23][N:12]([CH2:11][C:8]([OH:10])=[O:9])[CH2:13][CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH2:17][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:19][CH2:20]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: FC(F)(F)C1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)C(F)(F)F)CCN(CC(=O)O)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
12.94 g (115.44 mmol) of (1,1,1-trifluoro-2,3-epoxypropane) and 10 g (28.86 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 70° C. with exclusion of pressure. It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 1 with 5N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent=gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 10.81 g (68% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([CH2:25][F:26])[C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:24])(=[N:20][C:21](=[O:23])[NH2:22])=[O:19])=[CH:14][CH:13]=1)[OH:11].C([O:29][C:30](=O)[CH:31]([Cl:33])[Cl:32])C>CO>[C:21]([N:20]=[S:18]([C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]([OH:11])[C@H:9]([NH:8][C:30](=[O:29])[CH:31]([Cl:33])[Cl:32])[CH2:25][F:26])=[CH:17][CH:16]=1)([CH3:24])=[O:19])(=[O:23])[NH2:22]
Reactant: CS(=O)(=NC(N)=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Reactant: CCOC(=O)C(Cl)Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=NC(N)=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of (1R,2S)-2-Amino-3-fluoro-1-(4-(N-carbamoyl-S-methylsulfonimidoyl)phenyl)-propan-1-ol TFA salt (250 mg, 0.865 mmol) in Methanol (5 mL) is added TEA (0.175 mL, 1.73 mmol) followed by addition of ethyldichloroacetate (128.72 mL, 1.038 mmol) at room temperature. The resulting reaction mixture is stirred at room temperature for 16 h. Solvent is evaporated in vacuo and obtained crude is purified by combi-flash chromatography using 6% MeOH in DCM as an eluent to give 200 mg of title compound as off white solid. 1H-NMR (400 MHz, DMSO): δ 2.99 (s, 3H), 4.25-4.32 (m, 1.5H), 4.40-4.44 (m, 0.5H), 4.56-4.59 (m, 0.5H), 4.67-4.71 (m, 0.5H), 4.97 (bs, 1H), 6.05 (bs, 1H), 6.18 (m, 1H), 6.46-6.48 (m, 1H), 7.61 (d, J=7.52 Hz, 2H), 7.86 (d, J=8 Hz, 2H), 8.63-8.67 (m, 2H). LC-MS (m/z): M+H=399.8.