Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH2:21])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1([CH3:25])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([N:18]4[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH:21][C:34]4=[O:36])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc4c3C(C)(C)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-2-methylalaninamide (Intermediate 75, 7.5 mg) was dissolved in dry dichloromethane (1 ml). The reaction mixture was cooled down in an ice bath. Triethylamine (18.37 μl, 0.132 mmol) was added at 0° C. Then 0.5 ml of a solution of triphosgene in dry dichloromethane (0.012 mmol) was added dropwise. The solution was prepared with 7.18 mg of triphosgene dissolved in 1 ml of dichloromethane). The reaction mixture was stirred under argon during 10 min at 0° C., then during 30 min at room temperature. A saturated aqueous solution of NaHCO3 was added and the aqueous layer was extracted with dichloromethane 4 times. After drying over sodium sulphate, the solvents were removed under vacuum.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][S:15][CH:16]=[C:10]3[C:9]2=[O:17])[CH2:6][CH2:5][C:4](=[O:18])[NH:3]1.[H-].[Na+].[CH3:21]I.O>CN(C=O)C>[CH3:21][N:3]1[C:4](=[O:18])[CH2:5][CH2:6][CH:7]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][S:15][CH:16]=[C:10]3[C:9]2=[O:17])[C:2]1=[O:1]
Reactant: CI
Reactant: O=C1CCC(N2C(=O)c3cscc3C2=O)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCC(N2C(=O)c3cscc3C2=O)C1=O
Reaction time: 8 h

Procedure:
0.264 g of 5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione were dissolved in 10 mL anhydrous DMF, and 0.036 g of NaH (95%) were added. The reaction mixture was reacted at room temperature for 30 min, and 0.2 mL of CH3I were added. The reaction mixture was allowed to stir overnight. 100 mL of water were added, and the aqueous phase was extracted with ethyl acetate (3×30 mL). Organic phases were combined, washed with 30 mL of water and 30 mL of brine, dried over anhydrous MgSO4, filtered, and evaporated to dryness. A white solid (0.196 g) was obtained. 1H NMR (CDCl3): δ 7.91 (s, 2H), 4.93 (d, 1H, J=3 Hz), 3.22 (s, 3H), 3.04-2.94 (m, 1H), 2.83-2.71 (m, 2H), 2.11 (m, 1H); MS (m/z): 278 (M)+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Cl:14]>>[Cl:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCCCCBr
Product: ClCCCCCSc1ccccc1

Procedure:
Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-5-chloropentane.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1.[F:25]C1C=C(OCC2C=CC3C(=CC=CC=3)N=2)C=CC=1C(O)=O>>[F:25][C:10]1[CH:9]=[C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1[C:4]([N:3]([O:2][CH3:1])[CH3:24])=[O:23]
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1F
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1F

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting 2-Fluoro-4-(quinolin-2-ylmethoxyl)-benzoic acid provided the title compound. MS: (M+H m/z=341.2).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([OH:24])=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:25])=[N:6][CH:7]=1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[N:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=3[O:24][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[N:28]=3)=[CH:10][C:9]=2[F:25])=[N:6][CH:7]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Nc1cnc(-c2ccc(-c3ccc(C(F)(F)F)cc3O)cc2F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Nc1cnc(-c2ccc(-c3ccc(C(F)(F)F)cc3Oc3ccnc(N)n3)cc2F)cn1
Temperature: 120 °C

Procedure:
To a 5 mL vial were added a stir bar, 4′-(5-aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol (40 mg, 0.12 mmol), 4-chloropyrimidin-2-amine (17.8 mg, 0.14 mmol), DMSO (1 mL) and Cs2CO3 (52 mg, 0.16 mmol). The vial was flushed with nitrogen and heated for 15 hours at 120° Celsius. The reaction was diluted with 5 mL of ethyl acetate and 5 mL of brine. The aqueous layer was then extracted with ethyl acetate (3×10 mL), the combined organic extracts dried over Na2SO4, and concentrated to dryness. The crude product was purified by HPLC to give the title compound. MS (ESI): mass calcd. for C21H14F4N6O, 442.12; m/z found, 443.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.34 (s, 1H), 8.09-8.07 (d, J=1.4, 1H), 8.07-8.05 (d, J=7.0, 1H), 7.96-7.88 (m, 1H), 7.82-7.74 (d, J=1.6, 2H), 7.71 (s, 1H), 7.41-7.37 (dd, J=8.1, 1.7, 1H), 7.37-7.32 (dd, J=12.4, 1.7, 1H), 6.64-6.56 (d, J=7.0, 1H).
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10]Cl)([CH3:4])[CH3:3].[NH2:36][CH2:37][CH2:38][SH:39]>>[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10][S:39][CH2:38][CH2:37][NH2:36])([CH3:3])[CH3:4]
Reactant: NCCS
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Product: CC(C)OCCN(C(=O)CSCCN)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 1, 1-{4-[N-(2-isopropoxyethyl)-N-chloroacetylamino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine hydrochloride is reacted with cysteamine (=2-mercaptoethylamine), yielding 1-{4-[N-(2-isopropoxyethyl)-N-(2-aminoethylmercapto-acetyl)-amino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Reactant: COc1ccc(OB(O)O)c(Cl)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCc1nn2c(-c3ccc(OC)cc3Cl)cccc2c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
After dissolving 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (100 mg) in 1,2-dimethoxyethane (6 mL) and water (1 mL), 2-chloro-4-methoxyphenylboric acid (138 mg), tetrakis(triphenylphosphine)palladium(0) complex (86 mg) and barium hydroxide octahydrate (233 mg) were added and the mixture was heated and stirred at 80° C. for 3 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract washed with saturated aqueous sodium hydrogencarbonate and brine, in that order. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (90 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])C.[OH-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:26])=[O:3])=[O:25])=[C:18]([F:24])[CH:19]=1
Reactant: CCOC(=O)COc1cc(Cl)ccc1C(=O)NCc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)COc1cc(Cl)ccc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid ethyl ester (3.20 g, 7.20 mmol) in ethanol (36 mL, 0.2 M) was cooled to 0° C. and treated with aq NaOH (1.25 M, 28.8 mL, 36.0 mmol). After stirring for 30 min, the solution was warmed to room temperature and stirred an additional 4 h. Next, the solution was acidified to pH 1-2 with 2 N HCl, diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to give [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid as a white crystalline solid (2.91 g, 97%): mp 184-185° C.; Rf 0.31 (20% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 13.40 (br s, 1H), 9.05, (t, J=5.7 Hz, 1H), 7.83, (d, J=8.4 Hz, 1H), 7.48 (d, J=10.5 Hz, 1 Hz), 7.38-7.32 (m, 2H), 7.26 (d, J=1.8 Hz, 1H), 7.13 (dd, J1=8.4 Hz, J2=1.5 Hz, 1H), 4.91 (s, 2H), 4.49 (d, J=5.7 Hz, 2H). ESI-LC/MS m/z calcd for C16H12BrClFNO4: 416.6; found 418.0 (M+1)+. Anal. calcd for C16H12BrClFNO4: C, 46.13; H, 2.90; N, 3.36; Cl, 17.02. Found C, 46.04; H, 2.89; N, 3.31; Cl, 17.09.
Reaction SMILES: BrC1C=CC=C(C)C=1.[Li]CCCC.CCCCCC.COC(NCC[O:27][C@@H:28]([C:42]1[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=1)[C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1)=O>C1COCC1>[CH3:48][C:44]1[CH:43]=[C:42]([CH:47]=[CH:46][CH:45]=1)[C:28]([C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH2:30]1)=[O:27]
Reactant: COC(=O)NCCO[C@@H](c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc(C(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 125.8 %

Procedure:
To a solution of 1-bromo-3-methylbenzene (88.4 g, 0.52 mol) in anhydrous THF (550 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (210 mL, 0.52 mol). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-((R)-(2-(methoxycarbonylamino)ethoxy)(m-tolyl)methyl)piperidine-1-carboxylate (120 g, 0.44 mol) in anhydrous THF (500 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with EtOAc (3×400 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(3-methylbenzoyl)piperidine-1-carboxylate (168 g), which was used immediately for next step without purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([CH3:31])=[CH:24][C:23]=1[Cl:32]>>[Cl:32][C:23]1[CH:24]=[C:25]([CH3:31])[C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=1[NH:11][C:10]1[N:6]([CH2:5][CH:4]([O:18][CH2:19][CH3:20])[O:3][CH2:1][CH3:2])[N:7]=[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=1
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Reactant: Cc1cc(Cl)c(Br)cc1[N+](=O)[O-]
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])c(C)cc1Cl)OCC

Procedure:
Analogously to Example 13A/Step 1, from two reactions (273 mg and 1.58 g; 6.72 mmol in total) of the compound of Example 4A and 250 mg and 1.45 g (7.4 mmol in total) of 1-bromo-2-chloro-4-methyl-5-nitrobenzene gave, after 2 h of heating under reflux, a crude product which was purified by double chromatography on a Biotage system (in each case 50 g Snap column; mobile phase gradient hexane/ethyl acetate, from 20% ethyl acetate increasing rapidly to 100% ethyl acetate, then ethyl acetate/methanol, increasing slowly to 100% methanol). This gave 1.96 g (69% of theory) of the title compound.
Reaction SMILES: C[Si](Br)(C)C.[CH3:6][P:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[O:8]CCC1C=CC=CC=1>>[CH3:6][P:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[OH:17]
Reactant: CP(=O)(OCCc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Br
Product: CP(=O)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylsilylbromide (15 ml., 0.1 mole) is added portionwise to methylphenyl phosphinic acid, phenethyl ester (15.2 g.,0.1 mole) at a rate to maintain reflux temperature. Following the addition, the mixture is stirred one hour at ambient temperature. The volatiles are removed in vacuo. The addition of water (10 ml.) to the liquid residue (20.6 g.) results in the separation of a white solid. The mixture is stirred at ambient temperature overnight, followed by filtration, with a recovery of 14 g. of solid. It is recrystallized from dichloromethane (80 ml.) to give methylphenylphosphinic acid, 9.9 g. (72%), m.p. 133°-135°.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)=[O:16])[CH3:13].CN(CCN(C)C)C.[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[Cl:30])=[O:16])[CH3:13]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCNC(=O)c1ccsc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCNC(=O)c1ccsc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (44 mL, 57.2 mmol) was added dropwise to a -78° C. cooled solution of N-ethyl-3-thiophenecarboxamide (4.04 g, 26 mmol) and TMEDA (6.65 g, 57.2 mmol) in THF (100 mL). After stirring for 30 min at -78° C., a solution of hexachloroethane (13.54 g, 57.2 mmol) in THF (20 mL) was added dropwise. The resulting reaction mixture was warmed to RT over 1 h, quenched with dilute aq citric acid, and extracted with EtOAc (3×). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 3:7 EtOAc/hexanes to give 2.8 g of N-ethyl-2-chloro-3-thiophenecarboxamide as a yellow oil, a 57% yield.
Reaction SMILES: [OH:1]/[CH:2]=[C:3]1/[C:4](=[O:11])[CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH2:8]/1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:4]2([OH:11])[CH2:5][CH2:6][C:7]([CH3:9])([CH3:10])[CH2:8]/[C:3]/2=[CH:2]\[OH:1])=[CH:15][CH:14]=1
Reactant: CC1(C)CCC(=O)/C(=C/O)C1
Reactant: Clc1ccc([Mg]Br)cc1
Product: CC1(C)CCC(O)(c2ccc(Cl)cc2)/C(=C/O)C1

Procedure:
reacting the first protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide the first protected (2E)-1-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and isolating or not isolating the first protected (2E)-1-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(O)=O.C(Cl)Cl>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH3:11])[N:5]=1)[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1ccccc1N
Solvent: ClCCl
Solvent: O=CO
Product: CC(=Nc1ccccc1C)c1cccc(C(C)=Nc2ccccc2C)n1
Reaction time: 40 h
Yield: 45.9 %

Procedure:
One g of 2,6-diacetylpyridine and 3.0 ml of o-toluidine were added to an Erlenmeyer flask with 20 ml of methylene chloride. A stirbar and 5 drops of 97% formic acid were added, and the flask was sealed and the solution was stirred for 40 hours. The solvent was then removed in vacuo, and the flask was placed in the freezer at −30° C. The resulting viscous oil was washed with cold methanol, and a yellow solid formed and was isolated by filtration and identified by 1H NMR as the desired product (959 mg, 45.9%). 1H NMR (CDCl3): δ8.38(d, 2, Hpyr) 7.86(t, 1, Hpyr), 7.20(m, 4, Haryl) 7.00(t, 2, Haryl), 6.67(d, 2, Haryl) 2.32 (s, 6, N═C—CH3) 2.10(s, 6, CH3 aryl).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][C:11]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][C:13]=3[CH2:14][C:5]=2[N:4]2[CH:21]=[CH:22][N:23]=[C:3]12.O1CCOCC1>Cl>[O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][C:11]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][C:13]=3[CH2:14][C:5]=2[N:4]2[CH:21]=[CH:22][N:23]=[C:3]12
Reactant: CCOC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 4 h
Yield: 103.4 %

Procedure:
A suspension of 0.5 g of ethyl [4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl]acetate in 50 ml of 6N hydrochloric acid is heated at reflux for 2 hours. 25 ml of 1,4-dioxane are added to the mixture and reflux is continued for 4 hours. After returning to a temperature in the region of 20° C., the solid formed is filtered, washed with 5 ml of 1,4-dioxane and then dried under reduced pressure (1 mbar) at 60° C. 0.47 g of [4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl]acetic acid is thus obtained in the form of a hydrochloride monohydrate, the melting point of which is greater than 260° C. (Analysis; % Calculated C: 56.7, H: 3.81, Cl: 11.16, N: 13.23; % Found C: 56.7, H: 3.9, Cl: 10.9, N: 12.9).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:4]=1[N+:12]([O-])=O.C1C=CC=CC=1>O.C(O)C.[Fe]>[Cl:2][C:3]1[C:8]([Cl:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:4]=1[NH2:12]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(Cl)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: Nc1cc(F)c(F)c(Cl)c1Cl
Yield: 41.5 %

Procedure:
To a suspension of iron powder (1.9 g) in water (3 ml), with vigorous stirring at 50° to 60 ° C., was added concentrated hydrochloric acid (0.4 ml) slowly. After mixed with ethanol (7 ml), 2,3-dichloro-4,5-difluoronitrobenzene (2.47 g) in ethanol (3 ml) was added dropwise to the suspension at 54° to 66° C. during 20 minutes. After stirring for 4 hours at the same temperature, the hot reaction mixture mixed with benzene was filtered and the insoluble materials were washed with hot ethanol (5 ml) and with benzene (20 ml) successively. The filtrate and washings were combined and mixed with ice water. The resulting organic layer was collected, washed with water, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was purified by silica gel chromatography eluting with dichloromethane-n-hexane (1:3) to give the title compound (0.89 g) as colorless needles, mp 94°-97.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[S:16]([NH2:19])(=[O:18])=[O:17].CS[C:22](SC)=[C:23]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([NH:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[C:24]1=[O:39]>O1CCOCC1>[CH:36]1([CH2:35][NH:34][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]([OH:33])=[C:23]([C:22]3[NH:1][C:2]4[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[CH:4][C:3]=4[S:16](=[O:17])(=[O:18])[N:19]=3)[C:24]2=[O:39])[CH2:37][CH2:38]1
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(NCC2CC2)C1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A mixture of the product of Example 414A (78.1 mg, 0.272 mmol) and the product of Example 353B (91.0 mg, 0.272 mmol) in anhydrous dioxane (2.7 mL) was heated under reflux for 3 h. The reaction mixture was then cooled to 25° C. and concentrated under reduced pressure to yield an oily solid. The solid was triturated with methanol to yield the title compound (72.5 mg, 51%). 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=4.04 Hz, 2 H) 0.42 (m, 2 H) 1.00 (m, 1 H) 1.51 (s, 9 H) 2.85 (bd, J=4.78 Hz, 2 H) 6.45 (bs, 1 H) 7.44 (t, J=7.54 Hz, 1 H) 7.62 (d, J=8.82 Hz, 1 H) 7.69 (dd, J=8.82, 2.20 Hz, 1 H) 7.89 (m, J=7.91, 7.91 Hz, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.17 (m, 2 H) 9.93 (s, 1 H) 14.08 (s, 1 H) 15.15 (d, J=4.78 Hz, 1 H). MS (ESI−) m/z 524.0 (M−H)−. The sodium salt of the compound was prepared by reacting example 414B (3.9 mg, 0.0074 mmol) with 1 N sodium hydroxide solution (0.0074 mL, 0.0074 mmol) in 0.5 mL water and 0.5 mL tetrahydrofuran at room temperature for 1.2 h. The reaction mixture was then evaporated under a stream of nitrogen to provide the sodium salt (4.1 mg, 100% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.20 (m, J=5.52 Hz, 2 H) 0.46 (d, J=8.82 Hz, 2 H) 1.00 (m, 1 H) 1.50 (s, 9 H) 3.30 (m, 2 H) 5.96 (t, J=6.25 Hz, 1 H) 7.06 (t, J=7.17 Hz, 1 H) 7.20 (d, J=9.19 Hz, 1 H) 7.52 (m, 2 H) 7.67 (d, J=8.82 Hz, 1 H) 7.90 (s, 1 H) 8.06 (d, J=7.35 Hz, 1 H) 9.60 (s, 1 H) 16.22 (s, 1 H). MS (ESI+) m/z 543.1 (M+H+H2O-Na)+, 526.1 (M−Na)+, (ESI−) m/z 524.1 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([N:25]=[C:26]=[S:27])(=O)C1C=CC=CC=1.CO.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:26]([NH2:25])=[S:27])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(NC(N)=S)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3 g (13.5 mmol) (3-amino-benzyl)-carbamic acid tert-butyl ester (WO 9740028 A1) and 1.81 ml (13.5 mmol) benzoyl isothiocyanate in 60 ml THF was stirred at room temperature for 1 h and afterwards evaporated under reduced pressure. 80 ml MeOH and 5.6 g (40.5 mmol) potassium carbonate in 80 ml water were added and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layers were washed with saturated NaHCO3 solution and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with a gradient of hexane/ethyl acetate to yield after evaporation of the product fractions 3.56 g (94%) of the title compound as yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1)#[N:18]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:17]#[N:18])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: N#Cc1cccc(N=C=O)c1
Product: COc1ccc(NC(=O)Nc2cccc(C#N)c2)cc1-c1c(Cl)cnn1C
Yield: 64.9 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (55 mg, 0.23 mmol) was treated with 3-Cyanophenyl isocyanate (37 mg, 0.26 mmol) in a similar manner to Example 1.53, providing 57 mg (65%) of Compound 109: LCMS m/z (%)=382 (M+H35Cl, 100), 384 (M+H37Cl, 38). 1H NMR (400 MHz, DMSO-d6) δ: 9.02 (s, 1H), 8.85 (s, 1H), 7.98 (t, 1H), 7.68 (d, J=8 Hz, 1H), 7.62 (s, 1H), 7.59 (dd, J1=12 Hz, J2=2 Hz, 1H), 7.50 (t, 1H), 7.42 (t, 1H), 7.42 (d, J=4 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 3.78 (s, 3H), 3.62 (s, 3H).