Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][OH:23])=[O:16])[CH:12]=[CH2:13].Cl>ClCCl.C(OCC)(=O)C.[Cl-].[Na+].O.C(N(CC)CC)C>[CH2:11]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH:22]=[O:23])=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N1CCC[C@H]1CO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)N1CCCC1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
To a solution of oxalyl chloride (5.45 ml) in dichloromethane (100 ml) was added dropwise a solution of dimethyl sulfoxide (9.67 ml) in dichloromethane (10 ml) at -78° C. After stirring at -78° C. for 10 minutes, to the mixture was added dropwise a solution of (2S)-1-allyloxycarbonyl-2-hydroxymethylpyrrolidine (10.41 g) in dichloromethane (20 ml). After stirring at -78° C. for 10 minutes, to the mixture was added dropwise triethylamine (39.6 ml) and the resulting mixture was allowed to warm to 0° C. and diluted with ethyl acetate (400 ml) and brine (200 ml). After adjusting pH to around 5 with 4N hydrochloric acid, the organic layer was separated, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil of 1-allyloxycarbonyl-2-formylpyrrolidine (8.72 g), which was dissolved in toluene (100 ml). To this solution was added 3-triphenylphosphoranylidenebutan-2-one (17.4 g) and the mixture was allowed to stand at ambient temperature for 5 days. Evaporation of the solvent gave a residue which was taken up into ethyl acetate. The resulting precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel (300 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-6:4 V/V) to give (2S)-1-allyloxycarbonyl-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (9.00 g).
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[N:36]1([CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]5[CH:32]=[CH:31][S:30][CH:29]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: C1CCNC1
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Yield: 38.6 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (55 mg, 0.12 mmol) and pyrrolidine (42.6 mg, 0.60 mmol) were allowed to react in the presence of K2CO3 (84.6 mg, 0.24 mmol) and NaI (Cat. 5 mg). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (23.2 mg, 39%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.C1(N[C:14]([C:16]2[C:21]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCCl>[Cl:30][C:26]1[CH:27]=[CH:28][C:29]2[C:14](=[O:15])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[CH2:22][CH2:23][C:24]=2[CH:25]=1
Reactant: O=C(Nc1ccccc1)c1ncccc1CCc1cccc(Cl)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CCc2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorous pentachloride (95%, 97.5 g; 0.45 mol) was added to a solution of N-phenyl-3-[2-(3-chlorophenyl)ethyl]-2-pyridine carboxamide 4 (100 g; 0.30 mol) in dichloromethane (500 ml). The resulting mixture was stirred at room temperature for one hour. Aluminum chloride (158.5 g; 1.19 mol) was then added to the mixture followed by stirring at room temperature for one hour. The solution was then poured onto ice (500 g) and the resulting mixture heated to reflux for one hour before cooling to room temperature. The pH of the aqueous phase was adjusted to 14 with 10M sodium hydroxide (700 ml) and the resting suspension filtered through a sintered glass funnel. The collected solid was washed with dichloromethane (2×100 ml). The organic layer of the filtrate was separated and washed with 1M HCl (1×200+1×100 ml). The organic layer was concentrated to an oil under vacuum, toluene (100 ml) was added, and the mixture again concentrated under vacuum. The oil was dissolved in toluene (150 ml) and charcoal (3.5 g) was added. The mixture was filtered through a pad of celite followed by the addition of hexane (100 ml) to the filtrate. The mixture was cooled to 0° C. for one hour prior to filtration. The collected product was dried in a vacuum oven at 60° C. overnight. Yield=44.2 g (61%)
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC.O>CN(C=O)C>[N:7]1([C:4]2[N:3]=[C:2]([C:17](=[O:19])[CH3:18])[S:6][N:5]=2)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: Clc1nc(-n2ccnc2)ns1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1nc(-n2ccnc2)ns1
Temperature: 67.5 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A catalytic amount of dichloropalladium(II)bis(triphenylphosphine) (189 mg, 268 μmol) was added to a solution of 5-chloro-3-imidazol-1-yl-[1,2,4]thiadiazole (500 mg, 2.68 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (904 μL, 2.68 mmol) in DMF (10 mL) under a nitrogen atmosphere at r.t. prior to heating at 65-70° C. for 21 h. The reaction was then cooled to r.t., H2O (70 mL) was added, filtered through celite, and washed with EtOAc (200 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated to a yellow residue. The yellow residue was diluted with a 5:1 mixture of 5N HCl/THF (48 mL) and stirred at r.t. for a period of 2 hours prior to concentrating to a white residue. The crude product was diluted with EtOAc (100 mL), washed with 1M NaOH (75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated to a white solid. Purification was achieved using column chromatography (CH2Cl2 to 9:1 CH2Cl2/MeOH) to afford 398 mg (77%) of 1-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-ethanone as a white solid. [M+H]+ 195.35.
Reaction SMILES: [K].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[CH3:12][O:13][C:14]1[N:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=1>C(O)C>[CH3:12][O:13][C:14]1[N:19]=[C:18]([CH2:20][C:3](=[O:5])[C:2]([O:9][CH2:10][CH3:11])=[O:8])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=1
Reactant: COc1ccc([N+](=O)[O-])c(C)n1
Reactant: CCOC(=O)C(=O)OCC
Agent: [K]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1nc(OC)ccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
A roundbottom flask was charged with ethanol (540 ml) and (7.2 L). To this was added potassium (81.6 g, 2.09 mol) and mixture was stirred until all the potassium dissolved. Diethyl oxalate (306 g, 2.10 mol) was then added. The mixture was stirred for 5 minutes and then 6-methoxy-2-methyl-3-nitropyridine (320.0 g, 1.87 mol) was added. The resulting solution was stirred at room temperature for 36 hours. The slurry was filtered and the collected solids were washed thoroughly with ether and dried under reduced pressure. The solid was then suspended in 30 ml of water acetic acid was added until the pH=4. The solids that formed were collected by filtration to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-])=O)=[C:6]([CH:18]=1)[CH:7]=[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[O:9]1.[Cl-].[NH4+].O>C(O)C>[NH2:19][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][C:6]=1[CH:7]=[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[O:9]1
Reactant: O=C1OC(=Cc2cc(Cl)ccc2[N+](=O)[O-])c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)cc1C=C1OC(=O)c2ccccc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
A mixture of 3-(5-chloro-2-nitrobenzylidene)-2-benzofuran-1(3H)-one (808 mg), reduced iron (750 mg), ammonium chloride (72 mg), water (2.5 mL), and ethanol (25 mL) was stirred at 80° C. for 4 hours. The reaction mixture was filtered using Celite and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-(2-amino-5-chlorobenzylidene)-2-benzofuran-1(3H)-one (466 mg).
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:19][C:11]1[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([NH:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[N:7][CH:6]=1)=[O:20]
Reactant: NCCN1CCOCC1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(I)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(NCCN2CCOCC2)nc1
Temperature: 70 °C

Procedure:
N-(2-iodopyrimidin-5-yl)-2-methyl-5-nitrobenzamide (60 mg, 0.156 mmol), 2-morpholinoethanamine (˜200 mg, 1.5 mmol), and DIEA (0.041 mL, 0.234 mmol) were taken up in IPA (2.5 mL) in a 16×100 mm resealable pyrex tube and heated at 70° C. for 4 h. The mixture was concentrated and purified by preparative TLC (2.5% MeOH/CH2Cl2) to afford 2-methyl-N-(2-(2-morpholinoethylamino)pyrimidin-5-yl)-5-nitrobenzamide.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]21OCC[O:13]2.C(O)(C(F)(F)F)=O.C(Cl)Cl.O>C1(C)C=CC=CC=1>[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH2:1][C:2](=[O:13])[CH2:3][CH2:4]2)#[N:12]
Reactant: N#Cc1ccc2c(c1)CCC1(C2)OCCO1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)CCC(=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 122.1 %

Procedure:
A mixture of 3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-6′-carbonitrile (230 mg, 1.1 mmol), 20% TFA/CH2Cl2 (4 mL), and H2O (˜0.1 mL) was stirred at room temperature for 16 hours. TLC (50% EtOAc/hexanes) showed no starting material (Rf˜0.95) left and a new spot (Rf˜0.90) formed. The mixture was diluted with toluene (50 mL) and then concentrated in vacuo. The residue was diluted with toluene (50 mL) and concentrated again to give 0.23 g (100%) of 6-cyano-2-tetralone as an orange solid. 1H NMR (300 MHz, CDCl3): δ 7.55 (s, 1H), 7.53 (d, 1H, J=7.8 Hz), 7.24 (d, 1H, J=7.8 Hz), 3.64 (s, 2H), 3.11 (t, 2H, J=6.6 Hz), 2.58 (t, 2H, J=6.6 Hz). As shown by the 1H NMR, the product was >95% pure, thus it was used without further purification.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][CH2:11][C:10]2[N:9]=[CH:8][CH:7]=[N:6][C:5]1=2)=[N+]=[N-]>[Pd]>[N:9]1[C:10]2[CH2:11][CH2:12][CH2:13][CH:4]([NH2:1])[C:5]=2[N:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=NC1CCCc2nccnc21
Agent: [Pd]
Product: NC1CCCc2nccnc21
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
A Parr shaker flask was charged with 5-azido-5,6,7,8-tetrahydroquinoxaline (1.81 g, 10.33 mmol) and 10% palladium on carbon (10 wt % of Pd/C; 0.18 g). The reaction vessel was evacuated and filled with nitrogen. Methanol (30 mL) was added and the reaction was hydrogenated at 30 psi for 40 minutes. The reaction mixture was flushed with nitrogen and filtered through a plug of Celite® to provide 5,6,7,8-tetrahydroquinoxalin-5-ylamine as an orange liquid (1.54 g, 99%), which would rapidly turn dark brown. It was stored under an argon atmosphere at −20° C. 1H NMR (CDCl3): δ 1.62-1.79 (m, 1H), 1.80-2.18 (m, 4H), 2.18-2.30 (m, 1H), 2.91-3.01 (m, 2H), 4.07 (dd, 1H, J=8.4, 5.4 Hz), 8.32-8.38 (m, 2H); 13C NMR (CDCl3): δ 19.7, 31.7, 32.2, 51.5, 142.0, 142.5, 152.6, 155.4; MS m/z: 150 (M+H+), 133.
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
A mixture of 7.0 g (E)-3-[1-(4-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester with 200 ml dichloromethane and 21.0 ml TFA is stirred at ambient temperature for 24 h. The dichloromethane and TEA is evaporated and the residue is coevaporated with toluene for 3 times. By this method 6.0 g of the title compound is obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>>[CH:10]([NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)N
Product: CC(C)Nc1ccc(C#N)cc1

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 4-fluorobenzonitrile and isopropylamine.
Reaction SMILES: [C:1]([N:6]1[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][O:8][C:7]1=[O:17])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].CCN(C(C)C)C(C)C.CN1C(=O)CCC1.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH:39]=[O:40]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:34][C:35]([F:48])([F:49])[C:36]1[CH:37]=[C:38]([C@@H:39]([OH:40])[C@H:2]([CH:3]=[CH2:4])[C:1]([N:6]2[C@@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][O:8][C:7]2=[O:17])=[O:5])[CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1
Reactant: C/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To (4S)-3-[(2E)-but-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one (13.8 g, 59.7 mmol) in DCM (100 mL) was added TiCl4 (1M in DCM, 59.7 mL, 59.7 mmol) at −10° C. The resulting reaction solution was transferred by cannula to a flask containing DIPEA (11.26 mL, 64.5 mmol) and DCM (100 mL) at 10° C. NMP (11.49 mL, 119 mmol) was added via a syringe and the reaction mixture was aged for 1 hour before cooling to −40° C. 3,5-Bis(trifluoromethyl)benzaldehyde (17.3 g, 71.6 mmol) in DCM (25 mL) was added via a syringe and the reaction was allowed to warm to 0° C. over 1.5 hr. The reaction was quenched by addition of acetic acid (15 mL), saturated Rochelle's salt (50 mL) and HCl (1.0 M, 200 mL). The organic was separated and the aqueous was back extracted with DCM (50 mL). The organics were combined, washed with HCl (1.0 M, 100 mL), dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by column chromatography to give (4S)-3-{(2S)-2-[(S)-[3,5-bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enoyl}-4-phenyl-1,3-oxazolidin-2-one (20 g, 42.3 mmol) as crystalline solid. 1H NMR (500 MHz, CDCl3) δ7.86 (s, 2H), 7.83 (s, 1H), 7.4 (m, 5H), 5.7 (m, 1H), 5.4 (m, 1H), 5.31 (d, J=10.3 Hz, 1H), 5.28 (d, J=3.9 Hz, 1H), 5.10 (d, J=17.3 Hz, 1H), 4.8 (m, 1H), 4.7 (t, J=9.0 Hz, 1H), 4.3 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]([NH:13][NH:14][C:15](=O)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:11][CH:12]=2)[CH:4]=[N:3]1.N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N([Si](C)(C)C)=[N+]=[N-].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:16]([C:15]1[N:11]2[CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=[N:9][C:10]2=[N:13][N:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cn1cc(-c2cnc(NNC(=O)Cc3ccccc3)nc2)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: N#N
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3nnc(Cc4ccccc4)n3c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
124.00 mg of N′-[5-(1-methyl-1H-pyrazol-4-yl)-2-pyrimidyl]phenylacetohydrazide are suspended in 2.5 ml of tetrahydrofuran in an N2-flushed reaction vial provided with a magnetic stirrer, 127.86 mg of triphenylphosphine and 66.81 μl of azidotrimethylsilane are added, and 120.84 μl of diisopropylazo dicarboxylate are added. The mixture is stirred at RT for a further 2 h. The reaction mixture is adsorbed onto silica gel and chromatographed. The chromatography residue is crystallised using methanol, filtered off with suction and dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:10]/[CH:11]=[C:12](/[CH2:18][CH2:19][CH2:20][F:21])\[C:13]([O:15]CC)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C(O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10]/[CH:11]=[C:12](/[CH2:18][CH2:19][CH2:20][F:21])\[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C(=C\C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCF
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C/C=C(/CCCF)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-tert-Butyl 1-ethyl (Z)—(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate (50.0 mg, 0.12 mmol) and lithium hydroxide (29.7 mg, 1.24 mmol) in ethanol (0.5 mL) and water (0.5 mL) was stirred at r.t. for 24 h, 30 min at 60° C. (microwave irradiation), and 14 h at 40° C. (oil bath). The mixture was cooled down to r.t. and acidified to pH 2 by addition of 2 N aqueous hydrochloric acid. The ethanol was then removed under reduced pressure and the aqueous solution extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over sodium sulphate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge C18, 5 μm 150×19 mm, acetonitrile/water (0.1% TFA) gradient, 21 mL/min). Yield: 10.0 mg, 0.03 mmol, 25%.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:22][C:23]([CH3:25])=[O:24]>>[C:1]1([CH:11]=[CH:22][C:23](=[O:24])[CH3:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C=Cc1cccc2ccccc12
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
In a 250 ml single neck flask was charged 15.6 g (100 mmoles,1.0 eq) of 1-naphthaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 16.5 g of 4-(1-naphthyl)-3-buten-2-one as a faintly yellow oil in 84.3% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14](COCC[Si](C)(C)C)[C:15]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([C:26]5[CH:31]=[C:30]([F:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=5[CH2:35][CH3:36])=[CH:23][CH:24]=4)[N:19](C4CCCCO4)[N:18]=3)=[N:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:51]>CO>[ClH:51].[ClH:51].[ClH:51].[CH2:35]([C:27]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([F:32])=[CH:31][C:26]=1[C:22]1[CH:21]=[C:20]2[C:25]([C:17]([C:15]3[NH:14][C:11]4[CH2:12][CH2:13][NH:8][CH2:9][C:10]=4[N:16]=3)=[N:18][NH:19]2)=[CH:24][CH:23]=1)[CH3:36]
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2c(-c3nc4c(n3COCC[Si](C)(C)C)CCN(C(=O)OC(C)(C)C)C4)nn(C3CCCCO3)c2c1
Agent: Cl
Solvent: CO
Product: CCc1cc(OC)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Temperature: 60 °C

Procedure:
To a solution of 2-[6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (Preparation 23, 801 mg, 1.13 mmol) in methanol (20 mL) was added concentrated hydrochloric acid (12M, 8 mL) and the resulting solution was heated at 60° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to furnish the title compound (739 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[F:24][C:25]([F:41])([F:40])[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:36][CH2:35][CH:34]2[C:37]([O-])=[O:38])[CH2:29][CH2:28]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:37]([CH:34]2[CH2:35][CH2:36][N:33]2[CH:30]2[CH2:29][CH2:28][N:27]([CH2:26][C:25]([F:40])([F:24])[F:41])[CH2:32][CH2:31]2)=[O:38])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C([O-])C1CCN1C1CCN(CC(F)(F)F)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: [Li+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCN2C2CCN(CC(F)(F)F)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)azetidine-2-carboxylate 20G carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as an off-white solid (65%). MS ISP (m/e): 602.3 (100) [(M+H)]]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>CC(C)=O.[I-].[K+]>[CH3:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Cl)ccc1OCC(=O)C(C)(C)C
Yield: 79.1 %

Procedure:
283 g (2 moles) of 4-chloro-2-methylphenol, 300 g of potassium carbonate and 2 g of potassium iodide were suspended in 2 l of anhydrous acetone and the suspension was heated to the boil. 359 g (2 moles) of bromopinacolone were then gradually added dropwise, while stirring, and the reaction mixture was heated for 5 hours under reflux. Thereafter, first the solvent, and then the ketone were distilled off under reduced pressure. 381 g (79% of theory) of 1-(2-methyl-4-chlorophenoxy)-3,3-dimethyl-butan-2-one of boiling point 109°-112°C/0.1 mm were obtained.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH2:6]([O:8][CH2:9][CH2:10][NH2:11])[CH3:7]>C(O)(C)C>[CH2:6]([O:8][CH2:9][CH2:10][NH:11][CH2:1][CH:2]([OH:3])[CH2:4][OH:5])[CH3:7]
Reactant: CCOCCN
Reactant: OCC1CO1
Solvent: CC(C)O
Product: CCOCCNCC(O)CO
Reaction time: 15 h
Yield: 69.2 %

Procedure:
A solution of glycidol (15 g, 0.2 mol) in isopropanol (50 ml) was added dropwise under N2 at 70° C. to a solution of 2-ethoxyethylamine (53 g, 0.6 mol) in isopropanol (125 ml). After 15 hours, the isopropanol was removed under reduced pressure (20 mm) and the residue distilled at 120°-5° C. at 0.4 mm to yield 22.6 g (69%) of 1.