Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=[C:3]([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])[CH:2]=1.[CH:20](N(CC)C(C)C)(C)C>CO>[Cl:19][CH2:18][CH2:17][N:13]([CH2:14][CH2:15][Cl:16])[C:3]1[CH:2]=[CH:1][C:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:20])=[O:11])=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Solvent: CO
Product: COC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
A mixture of chlorambucil (600 mg, 2 mmol), HBTO (625 mg, 2 mmol), and N,N-diisopropylethylamine (300 uL, 2 mmol) was stirred in methanol at 55° C. for 18 hrs. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 50 mL water. The mixture was then extracted with EtOAc and the combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/CH2Cl2 (10:1) to provide the compound 27a (350 mg, 1.1 mmol, 55% yield) as a yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 7.20-7.05 (dd, 2H), 6.71-6.62 (dd, 2H), 3.75-3.70 (m, 4H), 3.69 (s, 3H), 3.64 (m, 4H), 2.58 (t, J=7.6 Hz, 2H), 2.35 (t, J=7.5 Hz, 2H), 1.93 (p, J=7.6 Hz, 2H). HRMS (ESI, positive) m/z calcd. for C15H22Cl2NO2 [M+H]+: 318.10221, found: 318.10216.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[C:33](OC2C=CC([N+]([O-])=O)=CC=2)=[O:34])=[C:7]([S:45]([CH3:48])(=[O:47])=[O:46])[CH:6]=1)#[N:4]>C(#N)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:13](=[O:32])[N:12]2[C:33]([NH:2][CH3:1])=[O:34])=[C:7]([S:45]([CH3:48])(=[O:46])=[O:47])[CH:6]=1)#[N:4]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN
Solvent: CC#N
Product: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Methylamine (2.0 M in tetrahydrofuran, 69 μL, 138 μmol) is added to a solution of 4-nitrophenyl 4-(4-cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 38, 30 mg, 46 μmol) in acetonitrile (1 mL). The mixture is stirred at room temperature for 20 min and purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.15% formic acid). Yield: 22 mg; ESI mass spectrum M+H]+=547, Retention time HPLC: 1.01 min (Z017_S04).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC#N>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:19]=[C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)cc2n1
Reactant: C1CNCCN1
Solvent: CC#N
Product: Nc1nc(N2CCNCC2)nc2cc(-c3ccco3)nn12
Temperature: 25 °C

Procedure:
18 mmol of 7-furan-2-yl-2-methanesulfonyl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (Maybridge plc, Trevillett, Tintagel, Cornwall, England) was suspended in 50 mL of CH3CN along with 5 eq. of piperazine. The reaction mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with H2O, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by chromatography (95% CH2Cl2, 4% MeOH, 1% Et3N) to afford 7-furan-2-yl-2-piperazin-1-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[NH:14][C:15](=[O:19])[CH:16]=NO>CCOC(C)=O>[Br:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:8]=1[NH:14][C:15](=[O:19])[C:16]2=[O:2]
Reactant: O=C(C=NO)Nc1cccc(F)c1Br
Reactant: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C1Nc2c(ccc(F)c2Br)C1=O
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A 2 L 3-neck flask with a temperature probe adapter was fixed with a mechanical stirrer, condenser, and temperature probe. The flask was charged with conc. sulfuric acid (79 mL, 1418 mmol) and was heated to 70° C.; solid N-(2-bromo-3-fluorophenyl)-2-(hydroxyimino)acetamide (719a; 12.34 g, 47.3 mmol) was then slowly added (exotherm) and the temperature raised to 100° C. The brown solution was stirred at 90° C. for 45 min. The heating mantle was replaced with an ice bath to cool the reaction mixture to RT; the brown solution was poured into a beaker containing ice (500 mL), diluted with EtOAc (200 mL), added to a separatory funnel, and extracted with EtOAc (2×150 mL); the combined organics were dried over Na2SO4 and concentrated to give 7-bromo-6-fluoroindoline-2,3-dione (11.53 g, 47.3 mmol, 100% yield) as a reddish solid. 1H NMR (400 MHz, CDCl3) δ ppm 6.91 (t, J=8.51 Hz, 1H) 7.63 (dd, J=8.22, 4.89 Hz, 1H) 7.99 (br. s., 1H). 19F NMR (377 MHz, CDCl3) δ ppm −90.65 (s, 1F). MS (ESI, pos. ion) m/z: 243.9/245.9 (M+1).
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[CH:15][N+:16]([O-:18])=[O:17]>N1C=CC=CC=1>[CH3:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[C:15]([N+:16]([O-:18])=[O:17])[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClSc1ccccc1
Reactant: CN1CCNC1=C[N+](=O)[O-]
Solvent: c1ccncc1
Product: CN1CCNC1=C(Sc1ccccc1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
14.6 g of phenylsulfenyl chloride was added dropwise to a cooled, stirred solution of 14.3 g of Compound 1 in 250 ml of pyridine. The mixture was allowed to stand overnight at room temperature, then excess pyridine was recovered on a rotary evaporator. The residue was treated with 250 ml of water and the mixture extracted with methylene chloride. The combined extracts were dried and the solvent evaporated to give a crystalline solid which was triturated with ethyl acetate, then ethanol, to yield 25, as a yellow solid, melting point: 170° - 173° .
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16]Cl>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[C:11]([Cl:16])=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCl
Reactant: CC(=O)Nc1cc(-c2ccccc2)no1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1onc(-c2ccccc2)c1Cl
Yield: 60.4 %

Procedure:
3-Phenyl-5-acetylaminoisoxazole (7) (2.022 g) was dissolved in tetrahydrofuran (50 ml), a solution of chlorine (850 mg) in carbon tetrachloride (8.8 ml) was added dropwise thereto, and the mixture was kept to react at room temperature and under ice-cooling for 30 minutes, respectively. After evaporation the resulting residue was subjected to column chromatography on silica gel (20 g) to give crystals (1.43 g) of 3-phenyl-4-chloro-5-acetylaminoisoxazole (8) from the ether fractions; mp. 141°-141.5° C. (recrystallized from ether-hexane).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]=[C:41]=[O:42])[CH3:32]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:41]([NH:40][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH2:31][CH3:32])=[O:42])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: CCOc1ccccc1N=C=O
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccccc1NC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 34.9 mg (0.21 mmol) of 2-ethoxyphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 10 mg (18.7% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:4]1[C:13](=O)[C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:19])=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: COc1cccc2c(=O)c(C(C)=O)c[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(Cl)c(C(C)=O)cnc12

Procedure:
3-Acetyl-8-methoxy-4(1H)-quinolone (4.23 g, 19 mmol) and phosphorus oxychloride (150 ml) were heated under reflux for 45 minutes, evaporated to small volume in vacuo, poured onto ice, and the mixture adjusted to pH 4 with sodium bicarbonate. Extraction with chloroform, drying and evaporation of the organic solution gave crude 3-acetyl-4-chloro-8-methoxyquinoline as a dark coloured oil (7.9 g), which was used without purification.
Reaction SMILES: Cl.[S:2]1[C:6]([NH2:7])=[N:5][CH:4]=[N:3]1.[O:8]=[C:9]1[CH2:14][N:13]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11][N:10]1[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[O:8]=[C:9]1[CH2:14][N:13]([C:15](=[O:20])[C:16]([F:18])([F:17])[F:19])[CH2:12][CH2:11][N:10]1[C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:7][C:6]2[S:2][N:3]=[CH:4][N:5]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ncns1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Nc2ncns2)cc1
Yield: 48 %

Procedure:
Synthesized according to general procedure 12, method A. The reaction was set up with 1,2,4-Thiadiazol-5-ylamine hydrochloride (0.56 g, 4.0 mmol), anhydrous pyridine (3.5 mL), and 4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonyl chloride (1.5 g, 4.0 mmol). The dark oil was purified via silica gel chromatography using 5% MeOH in CH2Cl2 followed by a second purification on silica gel using 80% EtOAc in hexanes to obtain the desired sulfonamide as a white solid (0.73 g, 1.92 mmol, 48% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=436.1; tR=2.27 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:19](N(OC)C)=[O:20])=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:25][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:19](=[O:20])[CH3:25])=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8-(3,5-difluorophenyl)-N-methoxy-N-methylquinoline-7-carboxamide (67 mg, 0.20 mmol) in tetrahydrofuran (0.5 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (0.87 mL, 1.2 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was used directly in next step. LCMS calculated for C17H12F2NO(M+H)+: m/z=284.1; found: 284.0.
Reaction SMILES: Br.Br[CH:3]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:4]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=O.[CH3:19][C:20]1[N:25]=[C:24]([NH:26][C:27]([NH2:29])=[S:28])[CH:23]=[CH:22][CH:21]=1>C(O)C>[CH3:19][C:20]1[N:25]=[C:24]([NH:26][C:27]2[S:28][C:3]([N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)=[C:4]([C:6]3[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=3)[C:9]#[N:10])[N:29]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(NC(N)=S)n1
Reactant: N#Cc1cccc(C(=O)C(Br)n2cncn2)c1
Agent: Br
Solvent: CCO
Product: Cc1cccc(Nc2nc(-c3cccc(C#N)c3)c(-n3cncn3)s2)n1
Temperature: 90 °C

Procedure:
3-(2-Bromo-2-[1,2,4]triazol-1-yl-acetyl)-benzonitrile hydrobromide (500 mg, 1.34 mmol) is dissolved in ethanol (5 ml). (6-Methyl-pyridin-2-yl)-thiourea (208 mg, 1.34 mmol) is added and the reaction heated to 90° C. for 2 hours. The precipitate is collected and washed with ethanol twice. The solid is suspended in water and basified with concentrated ammonium hydroxide and the resulting precipitate collected and washed with water to give the title compound after drying. Mass Spec (APCI+) 360.0, m.p. 236–237° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[NH:26][C:25]=2[CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:25]=2[CH:30]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4ccc(Cl)cc43)CC2)ccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 5-chloro-3H-benzooxazol-2-one (105 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 5-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (16): HPLC retention time, 2.50 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 436.3, found, 436.4.
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:8]=1[O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[N+:18]([O-])=O.CCOC(C)=O.O>CCO.Cl>[NH2:18][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=1[O:9][C:8]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:7]=1[F:6])[C:14]#[N:15]
Reactant: N#Cc1ccc(Oc2cc(F)ccc2F)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1ccc(Oc2cc(F)ccc2F)c(N)c1
Temperature: 70 °C
Yield: 72.1 %

Procedure:
A mixture of Tin (II) chloride dihydrate (18.238 g, 81.00 mmol) in EtOH (65.00 mL) and HCl (12 M, 10.00 mL) was stirred at 70° C. until the solution became clear. Compound 21 (5.60 g, 20.28 mmol) was then added over 10 min. The solution was kept slightly refluxing during addition. The reaction was monitored with TCL (25% EtOAc in hexanes, Rf=0.65). The reaction was complete after refluxing for 1.5 hrs, as indicated by the absence of the starting material (TLC). Water (80 mL) was added and the resulting solution was allowed to cool to room temperature. The desired product was precipitated out as a white solid during cooling. The mixture was further cooled and stirred for 30 min at 15° C. The resulting precipitation was collected via filtration under vacuum, washed with water, and dried under vacuum to yield compound 22 as a white solid (3.60 g, 99.0% HPLC purity, 63% yield). 1H NMR (500 MHz, DMSO-d6): δ 7.44 (m, 1H), 7.09 (m, 2H), 7.04 (m, 1H), 6.92 (dd, J1=2 Hz, J2=8 Hz, 1H), 6.78 (d, J=8 Hz, 1H), 5.65 (s, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([C:37]1([CH3:45])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:30]2=[O:46].CCOC(C)=O>CN(C)C=O>[CH3:45][C:37]1([N:31]2[C:30](=[O:46])[C:29]3[C:33](=[CH:34][CH:35]=[C:27]([CH2:26][NH:25][C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=4)=[O:11])[CH:28]=3)[C:32]2=[O:36])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CSc1ccc(C(=O)O)nc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A stirred mixture of 5-methylsulfanyl-pyridine-2-carboxylic acid (0.34 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (0-5% gradient, MeOH/CH2Cl2, 0-5% gradient, product eluted after 4.7 min). The product fractions were combined, concentrated and the residue was triturated in MeCN (50 mL) for 1.5 h. The product was isolated by filtration and dried in vacuo to give 5-methylsulfanyl-pyridine-2-carboxylic acid [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.52 g, 57% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.89 min (98.54%); mp: 210-212° C.; 1H NMR (DMSO-d6) δ 1.88 (s, 3H), 1.97-2.12 (m, 1H), 2.53-2.78 (m, 6H), 4.62 (d, J=6.2 Hz, 2H), 7.68-7.90 (m, 4H), 7.91-8.04 (m, 1H), 8.52 (d, J=1.7 Hz, 1H), 9.51 (t, J=6.3 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 13.93, 21.02, 28.57, 29.09, 42.35, 58.73, 121.75, 122.05, 123.15, 129.59, 131.34, 133.53, 133.82, 139.65, 145.00, 145.90, 147.39, 164.07, 167.73, 167.88, 172.15; LCMS: MH=453; Anal Calcd for C22H20N4O5S: C, 58.40; H, 4.46; N, 12.38. Found: C, 58.24; H, 4.33; N, 12.16.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]1[N:16]=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]3[CH:23]=1)[N:8]=[CH:7]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:76][C@@H:77]1[CH2:81][CH2:80][N:79]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:78]1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:16]1[C:15]([CH2:14][CH2:13][N:9]2[C:10](=[O:12])[C:11]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:76][C@@H:77]3[CH2:81][CH2:80][N:79]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:78]3)[CH:7]=[N:8]2)=[CH:23][N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=c1c2c(Cl)cccc2cnn1CCc1cn2ccccc2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2cccc3cnn(CCc4cn5ccccc5n4)c(=O)c23)C1
Temperature: 105 °C
Reaction time: 1 h
Yield: 24.73 %

Procedure:
A reaction tube was charged with 8-chloro-2-(2-(imidazo[1,2-a]pyridin-2-yl)ethyl)phthalazin-1(2H)-one (155 mg, 0.48 mmol), BINAP (17.83 mg, 0.029 mmol), tris(dibenzylideneacetone)dipalladium(0) (8.74 mg, 9.55 μmol) and cesium carbonate (311 mg, 0.955 mmol) in 1591 μl of toluene. The mixture was stirred for 1 h under argon. To this mixture, (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (89 mg, 0.477 mmol) was added. The reaction mixture was heated in a microwave at 105° C. for 20 h. After completion of the reaction, the reaction mixture was extracted with water and DCM. The organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography using a normal phase Companion® system (4 g gold, gradient elution: DCM to 10% methanol). Yield: 24.73%. LC-MS: m/e=475.2 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[C:9]([C:17]3[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:16])[F:15])[CH2:4][CH2:3]1.[CH3:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[C:9]([C:17]3[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]4[CH2:27][CH2:26][N:25]([S:38]([C:34]5[CH:35]=[CH:36][CH:37]=[C:32]([CH3:31])[CH:33]=5)(=[O:40])=[O:39])[CH2:24][CH2:23]4)[N:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:15])[F:16])[CH2:3][CH2:4]1
Reactant: CC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: Cc1cccc(S(=O)(=O)N2CCC(N3N=C(c4ccc(OC(F)F)c(OCC5CC5)c4)C(C)(C)C3=O)CC2)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B3*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:22]([OH:25])[C:23]#[CH:24].CC(O[K])=O>CN(C=O)C.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>[OH:25][CH2:22][C:23]#[C:24][C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C#CCO
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[K]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccnc1C#CCO)c1ccccc1C(F)(F)F
Temperature: 100 °C
Yield: 48 %

Procedure:
N-(3-chloropyrazin-2-yl)-2-(trifluoromethyl)benzenesulfonamide (1.35 g; 4.0 mmol; 1.00 eq.) and 2-propyn-1-ol (336 mg; 6.0 mmol; 1.5 eq.) were dissolved in 10 mL of DMF under nitrogen atmosphere. To the reaction mixture was added CH3COOK (588 mg; 6.0 mmol; 1.5 eq.) and Pd(PPh3)4 (232 mg; 0.2 mmol) under nitrogen. The reaction mixture was then heated at 100° C. under nitrogen for 2 hours. After removal of the solvent by distillation in vacuo, the residue was triturated with water (40 mL) and extracted with diethyl ether (3×30 mL). The organic layer was dried over MgSO4 and evaporated down. The crude product was purified by silica gel column chromatography using a mixture of hexane and AcOEt to give pure N-[3-(3-hydroxyprop-1-yn-1-yl)pyrazin-2-yl]-2-(trifluoromethyl)benzenesulfonamide as a yellowish solid (686 mg, 48% yield, 98% HPLC purity).