Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][O:19][CH3:20].[N+:21]([O-])([OH:23])=[O:22]>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: COCCOC(=O)c1ccc(OC)c(OCCOC)c1
Solvent: CC(=O)O
Product: COCCOC(=O)c1cc(OCCOC)c(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-methoxyethyl 4-methoxy-3-(2-methoxyethoxy)benzoate (15.05 g, 52.9 mmol) in AcOH (54 mL) under an atmosphere of N2 was added conc. HNO3 (13.5 mL) in one portion. The reaction was stirred at RT for 72 h. The mixture was poured into ice-water (ca. 800 mL) and extracted with EtOAc (2×400 mL). The combined organics were washed with water (2×200 mL) and brine (1×200 mL), dried (Na2SO4) and conc. in vacuo. The residue was azeotroped with heptane (2×300 mL) to remove residual AcOH giving 2-methoxyethyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate as a dark colored oil. (15.5 g, 47.1 mmol, 89%). HPLC retention time 6.24 mins.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH2:18]([O:20][C:21]([C:23]1([CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])[CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:18]([O:20][C:21]([C:23]1([CH2:29][CH:30]2[CH2:31][CH2:32]2)[CH2:24][CH2:25][N:26]([C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[O:16])[CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(CC2CC2)CCNCC1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(CC2CC2)CCN(C(=O)c2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 0.31 g (1.4 mmol) 4′-fluoro-biphenyl-4-carboxylic acid, 0.426 g (1.71 mmol) 4-cyclopropylmethyl-piperidine-4-carboxylic acid ethyl ester, hydrochloride, 0.552 g (1.71 mmol) TBTU and 1.23 mL DIPEA in 25 mL DMF was stirred at room temperature over night. After evaporation to dryness the residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 0.51 g (87%) of the title compound as light yellow viscous oil. MS ISP (m/e): 410.3 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25].[Na+].[I-].[CH3:28][C:29]1([CH3:41])[O:34][CH2:33][CH:32]([CH2:35]OS(C)(=O)=O)[CH2:31][O:30]1>C(O)(C)C.[OH-].[Na+]>[CH3:28][C:29]1([CH3:41])[O:34][CH2:33][CH:32]([CH2:35][O:1][C:2]2[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]3[S:17][C:16]([CH3:18])=[C:15]4[C:11]=3[CH2:12][C@H:13]3[C:19]([CH3:21])([CH3:20])[C@H:14]34)=[O:9])=[CH:4][C:3]=2[CH3:25])[CH2:31][O:30]1
Reactant: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Reactant: CC1(C)OCC(COS(C)(=O)=O)CO1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (28.8 mg, 0.08 mmol, Example 5 step b) in isopropanol (3.5 mL) and 2 N aq. NaOH (0.6 mL) is added a catalytic amount of NaI followed by methanesulfonic acid 2,2-dimethyl-[1,3]dioxan-5-ylmethyl ester (90 mg, 0.40 mmol, B. Xu, G. Kirschenheuter, A. F. Greslin, X. Cheng, J. Sennelo, M. Cattaneo, M. L. Zighetti, A. Chen, S.-A, Kim, H. S. Kim, N. Bischofberger, G. Cook, K. A. Jacobson, J. Med. Chem. 45 (2002) 5694-5709). The reaction mixture is shaken at rt for 8 h, diluted with 1 N aq. NaOH, and extracted twice with DCM. The organic extracts are dried over MgSO4, filtered and evaporated. The residue is purified by prep. HPLC to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-benzylamide (28 mg) as a colourless solid. LC-MS: tR=1.13 min, [M+1]+=484.34.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:21]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([S:17]([CH3:20])(=[O:18])=[O:19])[CH3:21])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1oc2cccc(NS(C)(=O)=O)c2c1C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(N(C)S(C)(=O)=O)c2c1C
Temperature: 80 °C
Yield: 100 %

Procedure:
To a mixture of the product of Example 36, Step 1, 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (438 mg, 1.47 mmol, 1 eq) and K2CO3 (430 mg, 3.11 mmol, 2.1 eq) in 4 mL of DMF under nitrogen was added 0.18 mL of iodomethane (2.89 mmol, 2 eq). The reaction mixture was sealed and heated to 80° C. for 18 h. After cooling to room temperature and work up, 4-(methanesulfonyl-methyl-amino)-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in pure form without further purification (100% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (t, J=7.1 Hz, 3 H) 2.8 (s, 3 H) 3.0 (s, 3 H) 3.4 (s, 3 H) 4.5 (q, J=7.1 Hz, 2 H) 7.2 (dd, J=7.6, 0.8 Hz, 1 H) 7.4 (m, 1 H) 7.6 (m, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.CON(C)[C:12](=[O:24])[CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([C:12](=[O:24])[CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Br)c1
Reactant: CON(C)C(=O)CCN(C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CN(CCC(=O)c1cccc(Cl)c1)C(=O)OC(C)(C)C

Procedure:
A solution of 1-bromo-3-chloro-benzene (57 g, 0.3 mmol) in dry THF (300 mL) was added drop wise to Mg (10.8 g, 0.45 mmol) at room temperature under N2. The mixture was stirred at refluxed for 1 h. The Grignard reagent was added drop wise to a solution of tert-butyl 3-(methoxy(methyl)amino)-3-oxopropyl(methyl)carbamate (37 g, 0.15 mmol) in dry THF (300 mL) at −78° C. After addition, the mixture was allowed to stir at room temperature overnight. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified through column chromatography. 1H NMR (CDCl3, 400 MHz) δ 1.42 (s, 9H), 2.89 (s, 3H), 3.18 (m, 2H), 3.62 (t, 2H), 7.42 (m, 1H), 7.52 (m, 1H), 7.82 (m, 1H), 7.91 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][CH2:30][CH:31]1[CH:36]([C:37]([NH:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:38])[CH2:35][CH:34]=[CH:33][CH2:32]1>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][CH2:30][CH:31]1[CH:36]([C:37]([NH:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:38])[CH2:35][CH:34]=[CH:33][CH2:32]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: O=C(NCCN1CCCCC1)C1CC=CCC1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1CC=CCC1C(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Triethylamine (0.96 ml) and octadecyl isocyanate (2.2 ml) were added to a solution of 6-(hydroxymethyl)-N-(2-piperidinoethyl)-3-cyclohexene-1-carboxamide (1.65 g) in methylene chloride (22 ml). After being stirred for 15 hours at room temperature, triethylamine (0.96 ml) and octadecyl isocyanate (2.2 ml) were further added to the reaction mixture and stirred for 5 hours at room temperature. The insoluble matters were filtrated out under a vacuum and washed with chloroform. The filtrate and washings were combined together and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=30:1-10:1), thereby yielding the entitled compound (2.59 g) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]([C:12]1[S:13][C:14]([S:31][CH3:32])=[C:15]([S:17]([C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23](Cl)=[C:22]([Br:30])[CH:21]=2)(=[O:19])=[O:18])[CH:16]=1)=[O:11].C([O-])(=O)C.[Na+]>O1CCOCC1>[CH3:8][O:9][C:10]([C:12]1[S:13][C:14]([S:31][CH3:32])=[C:15]([S:17]([C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:22]([Br:30])[CH:21]=2)(=[O:19])=[O:18])[CH:16]=1)=[O:11]
Reactant: Nc1ccccc1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c(Cl)c([N+](=O)[O-])c2)c(SC)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c(Nc3ccccc3)c([N+](=O)[O-])c2)c(SC)s1
Temperature: 80 °C
Yield: 97 %

Procedure:
A mixture of aniline (112 mg, 1.35 mmol), 4-(3-bromo-4-chloro-5-nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 318: step c) 53 mg, 0.11 mmol), and sodium acetate (16.5 mg, 0.2 mmol) in dioxane (3 mL) was heated at 80° C. for 24 h. The mixture was partitioned between EtOAc (50 mL) and 0.5 N HCl (10 mL) and the organic layer was further extracted with 0.5 N HCl (2×10 mL), NaHCO3 (10 mL), and brine (20 mL). Drying of the solution over sodium sulfate followed by concentration yielded the product (58 mg) which was used without further purification. 1H-NMR (CDCl3): δ 8.04 (s, 1H), 7.64 (d, 1H, J=2.1 Hz), 7.32 (d, 1H, J=1.9 Hz), 7.25 (m, 2H), 6.95 (m, 1H), 6.69 (m, 2H), 5.70) (s, 1H), 3.90 (s, 3H), 2.66 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4]1)[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[CH3:2]
Reactant: CCC1Nc2ccccc2-c2ccccc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Yield: 86.8 %

Procedure:
A solution of 6-ethyl-5,6-dihydrophenanthridine (14 g, 69.2 mmol) and 4-methoxybenzenesulfonyl chloride (17.2 g, 83 mmol) in pyridine (100 ml) was heated at 80° C. overnight. The solvent was evaporated in vacuo; and the crude product was purified by preparative column chromatography on silica gel, eluting with a gradient and mixture of dichloromethane-hexane (50:50 to 100:0). After evaporation of the solvent, the residue was crystallized from diethyl ether, yielding the title compound (22.8 g, 60.1 mmol, 87%) as a colorless, crystalline solid, which was characterized by LCMS (ES+, FA, CV=5) and 1H NMR.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH3:23])([O-:13])=[O:12].N1CCCCC1>C1(C)C(C)=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[CH:23][C:15]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=2[N+:11]([O-:13])=[O:12])=[CH:3][CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Solvent: Cc1ccccc1C
Solvent: C1CCNCC1
Product: COc1ccc(C=Cc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a 2 liter 3-necked round-bottomed flask equipped with a condenser, a Dean-Stark trap, a mechanical stirrer, nitrogen inlet, heating mantle, thermometer, and a Therm-o-watch® temperature controller, was added p-anisaldehyde (149.8 grams, 1.1 moles), 2,4-dinitrotoluene (182 grams, 1.0 mole), xylene (500 milliliters), and piperidine (50 milliliters, 0.5 mole). The resulting mixture was heated with the temperature on the Therm-o-watch® temperature controller set at 145° C. After stirring and heating for about 2 hours, approximately 20 milliliters of water had collected in the Dean-Stark trap. The reaction solution was allowed to cool to room temperature, and then further cooled with an ice water bath for an additional hour during which time the desired product crystallized from the solution. The solid material was filtered, rinsed with pentane, and dried in a vacuum oven at 100° C. for 12 hours to give 257.1 grams (85.6 percent of theory) of the desired product as a dark red crystalline solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:13][C:12]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[OH:29])=[N:11]1.[CH3:38][N:39]([CH3:44])[S:40](Cl)(=[O:42])=[O:41]>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:27][CH2:26][CH2:25][N:24]([S:40](=[O:42])(=[O:41])[N:39]([CH3:44])[CH3:38])[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH2:13][C:12]([C:28]([C:34]([F:35])([F:36])[F:37])([C:30]([F:31])([F:33])[F:32])[OH:29])=[N:11]1
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(N3CCCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Product: CN(C)S(=O)(=O)N1CCCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Example 410, except for using 1-(2,4-difluoro-phenyl)-5-[4-(homopiperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride prepared in Example 409; and using dimethylsulfamoyl chloride instead of methanesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[Cl:16]>[Pt].C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[Cl:16]
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: [Pt]
Solvent: CCO
Product: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reaction time: 0.83 h
Yield: 100 %

Procedure:
Under nitrogen, a Parr Shaker flask was charged with Pt/C 5% (135 mg) and ethanol (180 mL) and 4-(3-fluorobenzyloxy)-3-chloro nitrobenzene (13.5 g) was added. The reaction vessel was placed on a Parr Shaker Apparatus under 25 psi of H2 for 50 minutes. The catalyst was then removed by filtration through Celite and the filtrate concentrated to afford a light grey solid. The filtrate was triturated with diethyl ether and the solids collected by filtration (12.05 g, ˜100% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[Br-].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH2:13][Zn+]>C1COCC1.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>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:13][C:12]2[C:11]([F:10])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Fc1cccc(F)c1C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1Cc1ccc(Cl)nn1
Temperature: 80 °C
Yield: 47.4 %

Procedure:
To a solution of 3,6-dichloro pyridazine (7.39 g, 50 mmol) and tetrakis(triphenylphosphine)palladium (2.89 g, 2.5 mmol) in THF (500 mL) was added 2,6 difluoro benzyl zinc bromide (120 mL, 60 mmol). The reaction mixture was heated to 80° C. for 1.5 hours until the reaction was complete by TLC. The reaction was cooled to room temperature, filtered through celite, and concentrated in vacuo. The crude residue was recrystalized from ether to yield 5.7 g of the title compound.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.S=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1>C(O)C>[CH3:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5][NH:6][C:17]1[CH2:21][S:20][C:19](=[O:22])[N:18]=1
Reactant: CN(C)C(=O)CN
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
To a solution of N,N-dimethylglycinamide hydrochloride (5 g) and triethylamine (5.03 mL) in ethanol (20 mL) was added 4-thioxo-1,3-thiazolidin-2-one (4.81 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/THF) to give the title compound (4.68 g).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:22])[NH:9][N:10]=[C:11]([OH:21])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[C:18](=[O:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:25])=[N-]>CO>[C:1]1([NH:7][C:8](=[O:22])[NH:9][N:10]=[C:11]([O:21][CH3:25])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[C:18](=[O:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ncccc1C(O)=NNC(=O)Nc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=NNC(=O)Nc1ccccc1)c1cccnc1C(C)=O

Procedure:
A suspension of 2-acetylnicotinic acid 4-phenylsemicarbazone (compound 1) (0.50 g) in 20 ml of methanol is treated with diazomethane until the yellow color of the solution persists. The solvent is removed in vacuo to give methyl 2-acetylnicotinate 4-phenylsemicarbazone, m.p. 177°-178° (compound 53, Table C).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14](=[NH:16])[CH3:15])(=[O:12])=[O:11])[CH:6]=[C:7]([I:9])[CH:8]=1)#[N:2].N[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClC1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14](=[N:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:15])(=[O:12])=[O:11])[CH:6]=[C:7]([I:9])[CH:8]=1)#[N:2]
Reactant: Nc1ccccc1
Reactant: CC(=N)NS(=O)(=O)c1cc(I)cc(C#N)c1
Solvent: Clc1ccccc1
Product: CC(=Nc1ccccc1)NS(=O)(=O)c1cc(I)cc(C#N)c1

Procedure:
A solution of 367 mg. (1 mmole) of N-(3-cyano-5-iodophenylsulfonyl) acetamidine in 10 ml. of chlorobenzene is heated with 205 mg. (2.2 mmoles) of aniline and the reaction mixture heated to reflux for 3 hours. The reaction mixture is cooled in an ice bath and filtered to remove the precipitate of aniline hydrochloride. The filtrate is treated with hexane affording crystalline N-(3-cyano-5-iodophenylsulfonyl)-N'-phenyl acetamidine.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([F:11])[C:5]2=[C:4]([Cl:12])[N:3]=1.CCN(C(C)C)C(C)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+].C(Cl)Cl>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([F:11])=[CH:9][N:8]([S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[C:6]=2[N:7]=1
Reactant: Fc1cnc2[nH]c(Cl)nc(Cl)c1-2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Cl)nc(Cl)nc32)cc1
Reaction time: 24 h

Procedure:
A solution of 2,4-dichloro-5-fluoro-1H-pyrrolo[2,3-d]pyrimidine (1.65 g, 8.01 mmol, crude material from abovefl) in dichloromethane (100 ml) was treated with DIPEA (2.80 ml, 16.02 mmol) and p-toluenesulfonylchoride (1.756 g, 9.21 mmol) and stirred for 24 hours. The mixture was poured into saturated sodium bicarbonate/DCM and the organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography (10% EtOAc/Hex). The chromatographic residue (still containing multiple impurities) was further purified with a 65% isocratic MeCN mobile phase on a Luna C18 5 um, 21×150mm column, 20 mL/min, UV @275 nm. The final purity of 2,4-dichloro-5-fluoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine was estimated at 99.5% at 254 nm using the same method (1.128 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J=2.20 Hz, 1H), 7.96 (d, J=8.24 Hz, 2H), 7.47 (d, J=8.79 Hz, 2H), 2.34 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Br:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1.CC#N.O>CCCCO>[C:26]([NH:25][C:24]1[C:18]2[C:19](=[N:20][CH:21]=[C:16]([Br:15])[C:17]=2[N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)[NH:22][CH:23]=1)(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CC#N
Solvent: CCCCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccccc4)c23)C1
Temperature: 160 °C
Reaction time: 24 h
Yield: 43.9 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (162 mg, 0.81 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (90 mg, 0.27 mmol, Example 7, Step A) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours in a sealed tube. The reaction was concentrated to dryness. The residue was then purified by chromatography (SP4, C-18 25M+ column, 10-90% CH3CN/water gradient, 30 CV) to yield (R)-tert-butyl 1-(3-benzamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (61 mg, 44% yield) as a solid.
Reaction SMILES: Br[C:2]1[N:6]=[C:5](/[CH:7]=[CH:8]/[C:9]2[N:19]=[C:12]3[C:13]([CH3:18])=[N:14][CH:15]=[C:16]([CH3:17])[N:11]3[N:10]=2)[N:4]([CH3:20])[N:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:17][C:16]1[N:11]2[N:10]=[C:9](/[CH:8]=[CH:7]/[C:5]3[N:4]([CH3:20])[N:3]=[C:2]([N:21]4[CH2:25][CH2:24][CH2:23][C:22]4=[O:26])[N:6]=3)[N:19]=[C:12]2[C:13]([CH3:18])=[N:14][CH:15]=1
Reactant: Cc1ncc(C)n2nc(/C=C/c3nc(Br)nn3C)nc12
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ncc(C)n2nc(/C=C/c3nc(N4CCCC4=O)nn3C)nc12
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 47.6 %

Procedure:
An argon-purged mixture of (E)-2-(2-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)vinyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (case 30922, Expl. 9a) p 31) (56 mg, 168 μmol, Eq: 1.00), pyrrolidin-2-one (28.6 mg, 25.7 μl, 336 μmol, Eq: 2), cesium carbonate (76.4 mg, 235 μmol, Eq: 1.4), tris(dibenzylideneacetone)-dipalladium(0)/Pd2(dba)3 (3.07 mg, 3.35 μmol, Eq: 0.02) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xant-phos) (3.88 mg, 6.7 μmol, Eq: 0.04) in dioxane (3 ml) was heated in a closed vessel for 1.5 hours at 140° C. under argon atmosphere. Up to 4 additional portions of Pd2(dba)3 and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xant-phos) are added and heating continued for another 1.5 hours until HPLC shows complete conversion of the Aryl bromide. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using ethyl acetate/methanol 5-10% as eluent affording 1-{5-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-pyrrolidin-2-one (27 mg, 47.6%) as an off-white solid. MS: m/z=339.6 (M+H+), MP: 242.5° C.