Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[F:10][C:11]1[CH:12]=[C:13]([CH:18]2[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30](O)=[O:31])[CH:24]=3)[NH:19]2)[CH:14]=[C:15]([F:17])[CH:16]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][C:11]1[CH:12]=[C:13]([CH:18]2[C:27]([CH3:28])([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([NH:7][S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[O:31])[CH:24]=3)[NH:19]2)[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(F)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (650 mg, 5.36 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (210 mg, 5.36 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(3,5-difluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (210 mg, 0.67 mmol) and 1,1′-carbonyldiimidazole (220 mg, 1.34 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h. Then the above suspension of cyclopropanesulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(3,5-difluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (40 mg, 15%) as a white solid: LC/MS m/e calcd for C21H22F2N2O3S (M+H)+: 421.5, observed: 421.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O-:18])=[O:17])[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:19])[C:12]([CH3:20])([CH3:21])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)[O-])C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl [(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]acetate from Step A (170 mg, 0.501 mmol) in THF (2 mL) and H2O (1 mL) was added LiOH monohydrate (36 mg, 0.858 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 1 N HCl (1 mL, 1 mmol), concentrated in vacuo and dried to afford the title compound. MS: m/z=312 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[S:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]#[C:20][CH2:21][OH:22]>CC(C)=O>[OH:22][CH2:21][C:20]#[C:19][CH2:18][S:10][C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: OCC#CCCl
Reactant: S=C1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCC#CCSc1cc2ccccc2[nH]1
Reaction time: 1 h
Yield: 110.6 %

Procedure:
To a solution of 2-indolinthione (7.45 g) in acetone (75 ml) is added potassium carbonate (7.60 g). After stirring, 4-chloro-2-butyn-1-ol (5.48 g) is added thereto. The mixture is stirred at room temperature for 5 hours and filtered. The filtrate is condensed to remove the acetone completely. The residue is dissolved into diethylamine (10 ml), kept at room temperature for 1 hour and evaporated to remove the diethylamine aiming to remove excessive agents. The residue is dissolved in ether (250 ml), washed with water, 2 N hydrochloric acid, water and a saturated saline solution successively, dried and evaporated to give the title compound as an oil (12.0 g).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].CO.N(CC)CC>C(=O)=O>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)[CH3:18])[N:11]=1)([CH3:2])[CH3:3].[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)[CH3:18])[N:11]=1)([CH3:2])[CH3:3]
Reactant: CC(Nc1nccc(N2C(=O)OC[C@@H]2C(C)C)n1)c1ccc(N2CCCCC2)cc1
Agent: O=C=O
Solvent: CO
Solvent: CCNCC
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(N3CCCCC3)cc2)n1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@H](C)c2ccc(N3CCCCC3)cc2)n1

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (93 mg, 0.38 mmol) and 1-(4-(piperidin-1-yl)phenyl)ethanamine (410 mg, 2.01 mmol, 5.2 equiv) in DMSO (1 mL) was heated at 110° C. for 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 100%) provided (4S)-4-isopropyl-3-(2-((1-(4-(piperidin-1-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (57 mg) in 36% yield. A mixture of (4S)-4-isopropyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one was resolved on a column (AD-H 4.6×100 mm) using 5 to 55% MeOH with 0.2% Et2NH in CO2 to give (S)-4-isopropyl-3-(2-((R)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-((S)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:19](O)=[O:20].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl.O>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:19]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]([CH:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:12])[C:2]=2[CH3:1])=[O:20])=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: Cc1c(C(=O)O)c2cccnc2n1C(C)c1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3ccccc3)c3ncccc23)c(O)n1
Yield: 67.5 %

Procedure:
To a solution of 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (400 mg, 1.43 mmol) in dichloromethane (30 mL) were added 1-hydroxybenzotriazole (291 mg, 2.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (412 mg, 2.15 mmol) and triethylamine (434 mg, 4.30 mmol). The resultant mixture was stirred at room temperature for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (262 mg, 1.72 mmol) was added and the resultant mixture was stirred at room temperature for 16 hours. Water (50 mL) was added to the mixture. The mixture was extracted with dichloromethane (100 mL×2). The organic layer was concentrated in vacuo to provide crude product which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1-(1-phenylethyl)-1H-pyrrolo-[2,3-b]pyridine-3-carboxamide (400 mg, 67.6%) as a white solid. LRMS (M+H+) m/z: calcd 414.21. found 414. HPLC purity (214 nm): 94%. 1H NMR (300 MHz, CD3OD): δ 8.22-8.13 (m, 2H), 7.28-7.15 (m, 6H), 6.47-6.45 (m, 1H), 6.09 (s, 1H), 4.50 (s, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H), 2.02 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13]O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CS(Cl)(=O)=O>C(Cl)Cl.C(N(CC)CC)C>[CH:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])=[CH2:13]
Reactant: COc1ccc(S(=O)(=O)CCO)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 75.7 %

Procedure:
To a solution of 2-(4-methoxybenzenesulfonyl)ethanol (20 mmol) in dry DCM (20 mL), triethylamine (4 mL) was added. The reaction mixture was cooled to 0° C. followed by dropwise addition of methanesulfonyl chloride (3 mL). The reaction mixture was then stirred at room temperature for 12 h after which it was diluted with DCM (150 mL). The organic phase was washed with 10% aqueous HCl (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with hexanes/EtOAc (3:1 to 1:1) to give 5-ethenesulfonyl-2-methoxybenzene (3 g).
Reaction SMILES: [CH3:1][NH:2]N.[F:4][C:5]1[CH:6]=[C:7]([C:11](=[NH:14])OC)[CH:8]=[CH:9][CH:10]=1.[CH2:15]([O:17][CH:18]([O:23][CH2:24][CH3:25])[C:19](=[NH:22])OC)[CH3:16].C(O)(=O)C>C1COCC1.C(Cl)Cl>[CH2:15]([O:17][CH:18]([O:23][CH2:24][CH3:25])[C:19]1[N:2]([CH3:1])[N:14]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=2)[N:22]=1)[CH3:16]
Reactant: COC(=N)c1cccc(F)c1
Reactant: CNN
Reactant: CCOC(OCC)C(=N)OC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(OCC)c1nc(-c2cccc(F)c2)nn1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 21 %

Procedure:
MeONa (2.35 g, 41 mmol) was added to a stirred solution of 3-fluorobenzonitrile (50.0 g, 413 mmol) in methanol (300 mL). The mixture was stirred at room temperature for 3 days and concentrated in vacuo. The residue was dissolved in ether (300 mL), washed with water (2×150 mL), brine (150 mL), dried with Na2SO4, and concentrated in vacuo to afford 62.8 g (99%) of methyl 3-fluorobenzenecarboximidoate. Methylhydrazine (21.8 mL, 410 n mmol) was added to a stirred solution of methyl 3-fluorobenzenecarboximidoate (62.8 g, 410 mmol) in THF (350 mL). The mixture was stirred at room temperature for 3 days, then. Then methyl 2,2-diethoxyethanimidoate (66.1 g, 410 mmol) and acetic acid (37.5 mL, 656 mmol) were added. The mixture was stirred for 24 h. The reaction was diluted with CH2Cl2 (500 mL), and the formed precipitate was filtered off. The filtrate was washed with 10% citric acid (2×200 mL), water (300 mL), brine (200 mL), dried with Na2SO4, and concentrated in vacuo. The residue was subjected to flash chromatography on silica gel using 1% MeOH/CHCl3 as eluent to give 24.0 g (21%) of the title product.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH2:16])=[O:15].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>ClCCl>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[C:14]([NH2:16])=[O:15])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NC(=O)c1cccn1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cccn1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (3.10 ml, 22.4 mmol) is added to a suspension of 1-amino-1H-pyrrole-2-carboxylic acid amide (1.25 g, 10.0 mmol) in dichloromethane (13 ml). Then 4-bromo-benzoyl chloride (2.19 g, 10.0 mmol) is added slowly. The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is washed with water and 1 N HCl. The organic phase is evaporated to give crude 1-(4-bromo-benzoylamino)-1H-pyrrole-2-carboxylic acid amide as light orange solid, which is used as such in the next reaction; HPLC/MS 1.56 min (C), [M+H] 308/310.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[S:24](Cl)(=[O:26])=[O:25].O>O1CCOCC1>[Cl:22][C:21]1[C:16]([OH:15])=[C:17]([S:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:26])=[O:25])[CH:18]=[C:19]([Cl:23])[CH:20]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: O
Solvent: C1COCCO1
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4.2 g (0.02 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile in 40 ml of dioxane (containing 1.6 ml pyridine) is added a solution of 5.3 g (0.02 mol) of 2-hydroxy-3,5-dichlorobenzenesulfonyl chloride in 15 ml dioxane. The second solution is slowly added to the first over a 10-minute period. The reaction mixture (which takes on an orange color) is stirred for 2 hours at room temperature and then left for 16 hours. Water is added and the precipitate is filtered off and dried, giving the pink, fluffy 3-[4-(3,5-dichloro-2-hydroxy benzenesulfonamido)-benzenesulfonyl]acrylonitrile: ##SPC28##
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].N.O.[N-:18]=C=O>CO>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH2:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: [N-]=C=O
Agent: N
Solvent: O
Solvent: CO
Product: CC(C)(C)N=NC1(NC(N)=O)CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 9.25 grams (0.0442 moles) of 1-t-butylazo-1-isocyanatocyclohexane in 50 ml of methanol in a 250 ml 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, gas addition tube and dry ice condenser was added gaseous ammonia until a gentle ammonia reflux was maintained in the condenser. The reaction was stirred for 90 minutes at room temperature, poured into 300 ml water and the solid that formed was filtered off. The filter cake was air dried leaving 9.0 grams (90% crude yield) of a white powder. The product melted at 115°-117° C. and its infrared spectrum contained a strong carbonyl band at 1670 cm-1 and sharp NH bands at 3250 cm-1 3330 cm-1 and 3440 cm-1. The isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][N:16]2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH3:12])C1C=CC=CC=1.CSC>C(O)(C(F)(F)F)=O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH:11]([NH2:10])[CH3:12]
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2cccnn2c1-c1ccccn1
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1nc2cccnn2c1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.5 %

Procedure:
The mixture of [1-(3-pyridin-2-yl-imidazo[1,2-b]pyridazin-2-yl)-ethyl]-carbamic acid benzyl ester (600 mg, 1.6 mmol) and dimethylsulfide (1.2 mL) in TFA (7.5 mL)) was stirred at rt overnight. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide 1-(3-pyridin-2-yl-imidazo[1,2-b]pyridazin-2-yl)-ethylamine (450 mg): LC-MS (ESI) m/z 240.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4](Br)[C:5](Br)=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[OH-:16].[Na+]>[Zn]>[C:8]([OH:16])(=[O:9])[C:7]1[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]([OH:10])=[O:12]
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: [OH-]
Agent: [Na+]
Agent: [Zn]
Product: O=C(O)c1ccccc1C(=O)O
Reaction time: 1 h
Yield: 97 %

Procedure:
Example 1 was repeated using tetrabromophthalic anhydride with 72 wt % zinc and 20% aqueous NaOH. After one hour at 60° C., 97% phthalic acid was produced. This example shows that the process of this invention is ineffective in selectively removing bromine.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=1)[C:43]([NH:45][CH3:46])=[O:44]>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:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[CH:49]=[CH:48][CH:47]=[C:42]([C:43]([NH:45][CH3:46])=[O:44])[CH:41]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CNC(=O)c1cccc(Br)c1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 32.9 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.44 g), 3-bromo-N-methylbenzamide (1.10 g) and tetrakis(triphenylphosphine)palladium(0) (0.21 g), the title compound (1.00 g) was obtained as a pale-yellow amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:21]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Product: NC(=O)c1c(NC(=O)c2ccccc2F)ncn1Cc1ccccc1
Yield: 97 %

Procedure:
An amidation reaction and post-treatment were carried out according to the conditions of Example 1, using 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain a crude amide product. The crude amide product was purified by suspension in hot methanol to obtain 1.69 g of 4-(2-fluorobenzoylamino)-1-benzyl-5-imidazolecarboxamide (yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:29](O)=[O:30])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:42][CH2:43][CH3:44])[C@H:34]([OH:41])[C:35]([NH:37][CH:38]1[CH2:40][CH2:39]1)=[O:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:29]([NH:32][C@@H:33]([CH2:42][CH2:43][CH3:44])[C:34](=[O:41])[C:35]([NH:37][CH:38]3[CH2:40][CH2:39]3)=[O:36])=[O:30])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Cl)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Cl)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2,4-dichlorophenylsulfonyl)pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide in step 1. MS (m/e)=670.11 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:23][NH:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30]2[C:31]3[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:26]1>CN1C(=O)CCC1.CCOC(C)=O>[CH3:12][N:11]([CH3:13])[S:8]([C:5]1[CH:6]=[N:7][C:2]([N:24]([CH3:23])[C@@H:25]2[CH2:29][CH2:28][N:27]([C:30]3[C:31]4[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:26]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)c1ccc(Cl)nc1
Reactant: CN[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(c1ccc(S(=O)(=O)N(C)C)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 200 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To a solution of 6-chloro-N,N-dimethylpyridine-3-sulfonamide (1 mmol) and DIPEA (2.5 mmol) in NMP (2 mL) was added (R)—N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.5 mmol). The reaction mixture was stirred at 200° C. for 60 minutes in microwave reactor. After cooling to room temperature, the mixture was diluted with EtOAc, washed with brine, dried, filtered, and concentrated. The residue was purified by chromatography with MeOH/H2O to give the title compound in yellow in 8% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:25][C:24]([CH3:26])=[C:23]4[C:19]=3[CH2:20][C@H:21]3[C:27]([CH3:29])([CH3:28])[C@H:22]34)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][OH:8].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:1][C:2]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:25][C:24]([CH3:26])=[C:23]4[C:19]=3[CH2:20][C@H:21]3[C:27]([CH3:28])([CH3:29])[C@H:22]34)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][S:41]([CH3:40])(=[O:43])=[O:42]
Reactant: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
At 0° C., a solution of 3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propan-1-ol (170 mg, 0.40 mmol) and DIPEA (0.11 mL, 0.64 mmol) in DCM (5 mL) is treated with methanesulfonyl chloride (0.04 mL, 0.48 mmol). The reaction mixture is stirred at 0° C. for 30 min, then at rt for 1 h before it is diluted with DCM (15 mL) and washed with 0.1 N aq. NaOH (20 mL) followed by 10% aq. citric acid solution (20 mL). The organic layer is dried over Na2SO4 and evaporated to dryness to give methanesulfonic acid 3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propyl ester (185 mg) as a beige resin; LC-MS: tR=1.23 min, [M+1]+=503.20.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[C:9][Si](C)(C)C)=[CH:6][N:5]=[C:4]([NH2:14])[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:8]([C:7]1[C:2]([CH3:1])=[CH:3][C:4]([NH2:14])=[N:5][CH:6]=1)#[CH:9]
Reactant: Cc1cc(N)ncc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(N)cc1C

Procedure:
The title compound is synthesized according to general procedure GP3 starting from to 1.8 g (8.8 mmol) 4-methyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 609 mg (4.4 mmol) K2CO3 in 315 mL MeOH. The product is purified by chromatography on silica gel using a DCM/MeOH gradient. Yield: 1.0 g (86%).