Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:27])[C:23]3[C:24]4[N:15]([C:16](=[O:26])[CH:17]=[N:18][C:19]=4[CH:20]=[CH:21][C:22]=3[F:25])[CH2:14]2)(=O)=O)=CC=1.[O:28]1[C:37]2[CH:36]=[C:35]([CH2:38][N:39]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=[CH:33][C:32]=2[O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:28]1[C:37]2[CH:36]=[C:35]([CH2:38][N:39]([CH:47]3[CH2:52][CH2:51][N:50]([CH2:12][C:13]4([OH:27])[C:23]5[C:24]6[N:15]([C:16](=[O:26])[CH:17]=[N:18][C:19]=6[CH:20]=[CH:21][C:22]=5[F:25])[CH2:14]4)[CH2:49][CH2:48]3)[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=[CH:33][C:32]=2[O:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)cnc4ccc(F)c2c43)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CC2(O)Cn3c(=O)cnc4ccc(F)c2c43)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a mixture of (7-fluoro-6-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl 4-methylbenzenesulfonate (0.093 g, 0.24 mmol) in ethanol (3 mL) was added 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)4-piperidinylcarbamate (for a synthesis see WO 2004058144 Example 99(h)) (78.5 mg, 0.22 mmol), then sodium carbonate (71.5 mg, 0.68 mmol). The reaction mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was placed directly onto the top of a 20 g silica gel column and chromatographed eluting with a 0-100% ethyl acetate in petrol gradient, then with a 0-50% methanol in ethyl acetate gradient to afford the product (70 mg, 52%).
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[NH2:16])([CH3:12])([CH3:11])[CH3:10].[CH:22](OCC#N)=[O:23]>ClCCl>[C:9]([O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH:18]([CH3:19])[CH3:20])[NH:16][CH:22]=[O:23])([CH3:12])([CH3:11])[CH3:10]
Reactant: N#CCOC=O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The preparation was carried out analogously to W. Duczek et al., Synthesis, 37-38 (1996). A solution of 4.04 g (40 mmol) of triethylamine in 10 mL of dichloromethane was added at 0° C. to a solution of 8.94 g (40 mmol) of L-leucine tert-butyl ester hydrochloride and 3.4 g (40 mmol) of cyanomethyl formate in 60 mL of dichloromethane. The reaction solution was allowed to warm to room temperature, stirred overnight at room temperature and then washed twice with saturated NaCl solution. The phases were separated and the organic phase was dried over magnesium sulfate. After filtration and removal of the solvent in vacuo, the residue obtained was distilled in vacuo. Yield: 7.5 g (87%). Boiling point: 118° C./2.7 Pa (0.02 torr).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:9]=12)#[N:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2OC)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Cn1ccc2c(O)c(C(=O)NCC(=O)O)nc(C#N)c21

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(2-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 381 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:55][C:56]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)=[O:57].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:55][C:56]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[O:57])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]c2c1
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(CC(=O)N3CCOCC3)c2c1
Temperature: 90 °C

Procedure:
A mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.139 mmol), 2-chloro-1-morpholinoethanone (27 mg, 0.166 mmol) and K2CO3 (58 mg, 0.417 mmol) in dry DMF (20 mL) was heated to 90° C. for 3 hours. After cooling to room temperature, ethyl acetate (100 mL) was added, and the solution was washed with water (3×10 mL) and brine (2×10 mL). The combined organic layers were dried over Na2SO4, concentrated to give the residue which was used into the next step without further purification. LCMS: (M+H)+=848.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:40]=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[S:45]([C:41]2[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=2)(=[O:47])=[O:46])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1CN(S(=O)(=O)c2cccnc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (30.2 mg, 0.071 mmol) in CH2Cl2 (3 mL) was added DIPEA (29.7 mg, 0.230 mmol) and pyridine-3-sulfonyl chloride hydrochloride (22.8 mg, 0.106 mmol, Acme Bioscience). It was stirred at rt for 3 hrs under argon. More DIPEA (29.7 mg, 0.230 mmol) and pyridine-3-sulfonyl chloride hydrochloride (Acme Bioscience, 25.2 mg, 0.118 mmol) were added. After 4 hrs the reaction mixture was extracted with EtOAc, washed with water, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The reaction mixture was then purified by flash column to give rac (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-1-(pyridine-3-sulfonyl)-pyrrolidine-3-carbonitrile (20.3 mg, 50.4%). HRMS (ES+) m/z Calcd for C27H25Cl2F2N3O2S+H [(M+H)+]: 564.1086; Found: 564.1087.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.[Cl:15][C:16]1[S:20][C:19]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26](O)[N:27]([CH2:34][C:35]2[CH:36]=[C:37]([CH:47]=[CH:48][CH:49]=2)[CH2:38][NH:39]C(=O)OC(C)(C)C)[C:28]3=[O:33])=[O:22])=[CH:18][CH:17]=1>ClCCl>[NH2:39][CH2:38][C:37]1[CH:36]=[C:35]([CH:49]=[CH:48][CH:47]=1)[CH2:34][N:27]1[CH2:26][C:25]2[C:29](=[CH:30][CH:31]=[CH:32][C:24]=2[NH:23][C:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)=[O:22])[C:28]1=[O:33]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2O)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(CN2Cc3c(NC(=O)c4ccc(Cl)s4)cccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.21 ml (2.7 mmol) of TFA and 0.07 ml (0.45 mmol) of triethylsilane are added dropwise to a solution of 181 mg (purity 66%, 0.22 mmol) of tert-butyl 3-[(4-{[(5-chloro-2-thienyl)carbonyl]amino}-3-hydroxy-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzylcarbamate in 4.5 ml of dichloromethane. The solution is stirred at room temperature overnight and then concentrated and dried under high vaccum. The residue is taken up in dichloromethane/methanol and the mixture is washed with 1N sodium hydroxide solution, dried over magnesium sulfate and concentrated. Ether is added to the residue, the mixture is filtered off with suction and the product is dried under high vacuum. Yield: 84 mg (90.7% of theory); MS (DCI, NH3): m/z (%)=412 (M+H, 100); HPLC (Method 2): rt (%)=6.25 (80).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si](C)(C)[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.Cl>C(O)C>[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=1)#[CH:9]
Reactant: C[Si](C)(C)C#Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
Add potassium carbonate (307 mg, 2.22 mmol) to a solution of trimethyl-(3-trifluoromethylphenylethynyl)-silane (1.07 g, 4.42 mmol) in ethanol (15 mL). Stir at room temperature for 16 h. Neutralized with 10% aqueous hydrochloric acid solution. Add water and extract the product with hexanes. Evaporate hexanes slowly in a cool water bath (<15° C.) to give the title compound (580 mg, 77%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].F[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].O>C1(C)C=CC=CC=1>[CH3:5][C:3]1[O:4][C:12]2[C:13]([C:14](=[O:15])[C:2]=1[C:1]([O:7][CH3:8])=[O:6])=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: O=C(Cl)c1ccccc1F
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C)oc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a dried flask, a solution of methyl acetoacetate (2.16 mL, 20.0 mmol) in toluene (100 mL) was treated with sodium hydride (60% mineral oil dispersion, 880 mg, 22.0 mmol). The resulting mixture was stirred at rt for 10 min, and then a solution of 2-fluorobenzoyl chloride (2.23 mL, 20.0 mmol) in toluene (50 mL) was added over about a 1 min. period. The resulting mixture was heated at reflux for 24.5 h, and then poured into water (200 mL). The mixture was extracted twice with ether (50 mL each). The combined organic phases were dried over sodium sulfate and concentrated under vacuum to provide a viscous yellow oil, which crystallized. The solid was recrystallized from a ethyl acetate/hexane solution to provide methyl 2-methyl-4-oxo-4H-chromene-3-carboxylate as off-white crystals in two crops (2.10 g, 48%). 1H NMR (400 MHz, CDCl3) δ ppm 2.53 (s, 3 H) 3.94 (s, 3 H) 7.42 (m, 2 H) 7.67 (ddd, J=8.5, 7.0, 1.8 Hz, 1 H) 8.21 (dd, J=7.9, 1.8 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2>>[NH:23]1[C:24]2[C:20](=[CH:19][C:18]([NH:17][C:10](=[O:12])/[CH:9]=[CH:8]/[C:7]3[C:2]([CH3:1])=[N:3][C:4]([C:13]([F:16])([F:15])[F:14])=[CH:5][CH:6]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Cc1nc(C(F)(F)F)ccc1/C=C/C(=O)O
Product: Cc1nc(C(F)(F)F)ccc1/C=C/C(=O)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoic acid, Example 82(b), (120 mg, 0.50 mmol) and 5-aminoindole (66 mg, 0.50 mmol, Aldrich) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a yellow solid. MP 231° C. MS (ESI, pos. ion) m/z: 346 (M+1).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[CH2:10]([O:13][CH:14]([CH3:19])[C:15]([O:17]C)=O)[CH:11]=[CH2:12].O>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:15](=[O:17])[CH:14]([O:13][CH2:10][CH:11]=[CH2:12])[CH3:19]
Reactant: CNOC
Reactant: C=CCOC(C)C(=O)OC
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C=CCOC(C)C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of N-methyl-O-methyl hydroxylamine hydrochloride (10.0 g, 104 mmol, 2 equiv) in dichloromethane (100 mL) was treated with trimethylaluminum (52.0 mL, 104 mmol, 2 equiv) at 0° C. After stirring for 1 hour at 0° C., a dichloromethane (50 mL) solution of (±)-methyl 2-(prop-2-en-1-yloxy)propanoate (7.50 g, 52.0 mmol) was added over 15 minutes. The mixture was warmed to ambient temperature and stirred for an additional 14 hours. The mixture was treated with water (500 mL) and extracted with dichloromethane (2×300 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to provide the titled compound.
Reaction SMILES: [CH2:1](N(C1C(C)=CC2C(C)CCC(C)(C)C=2C=1)C1C=CC(C(OCC)=O)=CC=1)C.C([N:31]([C:43]1[C:52]([CH3:53])=[CH:51][C:50]2[C:49]([CH3:55])([CH3:54])[CH2:48][CH:47]=[C:46]([CH3:56])[C:45]=2[CH:44]=1)[C:32]1[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1)C.C(O)C.[OH-].[K+]>O>[CH2:56]([C:46]1[C:45]2[CH:44]=[C:43]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=3)[C:52]([CH3:53])=[CH:51][C:50]=2[C:49]([CH3:54])([CH3:55])[CH2:48][CH:47]=1)[CH3:1]
Reactant: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)(C)CC=C3C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CC=C3CC)cc1
Temperature: 60 °C
Yield: 92 %

Procedure:
General Procedure E To a solution of ethyl 4-[ethyl(3,5,8,8-tetramethyl-5,6-dihydronaphthalen-2-yl)amino]benzoate, (Compound 19, 0.17 g, 0.45 mmol) and 5 mL of absolute ethyl alcohol was added aqueous 5 M KOH (2 mL). The resulting solution was heated in an 60° C. bath for 24 h. The solution was cooled to room temperature, diluted with water and washed once with 2:1 hexane:ethyl acetate solution, and the layers were separated. The aqueous layer was acidified with HCl 2 N to pH=0-1 and the product extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed to give 0.042 g (92%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[OH-].[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccncc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 96.3 %

Procedure:
A mixture of 4-methoxy-3-nitroaniline (168 mg, 1 mmol) and Isonicotinoyl chloride hydrogen chloride (267 mg, 0.2 M in 1.5 mmol) in pyridine (1 mL) is sealed in a microwave reactor and heated at 100° C. under microwave radiation for 5 mins. Then 1N NaOH aqueous solution is added to the reaction mixture. After stirring at room temperature for several minutes, the mixture is filtered. The solid is washed with H2O and air dried to give 263 mg of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([O:16][CH2:17][CH2:18]Br)[NH:14][C:13]1=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:13](=[O:20])[N:14]2[C@@H:15]1[O:16][CH2:17][CH2:18]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1OCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(N[C@@H]1C(=O)N2CCO[C@H]12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A mixture of (3S,4R)-3-benzyloxycarbonylamino-4-bromoethoxy-azetidin-2-one (2.04 g, 5.945 mmole) and powder K2CO3 (903 mg, 6.54 mmole) in DMSO (20 ml) was stirred at room temperature overnight and then diluted with ethyl acetate, washed with cold water, brine, and dried over sodium sulfate. After removal of the solvent, 1.43 g of the title compound was obtained.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH2:18][CH2:19][CH2:20][CH2:21][OH:22].Cl>C1COCC1>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: NCCCO
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCCO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (2.80g, 10 mmol) in 100 ml of THF was cooled to ice temperature and stirred in an ice-bath while a solution of 3-amino-1-propanol (99%) (1.67g, 22 mmol) was added dropwise over a period of 45 minutes. Stirring in the ice-bath was continued for 30 minutes. The reaction miture than was acidified by addition of 3.0 ml of 1.2N HCl. The THF was evaporated under reduced pressure and the residue taken up in 100 ml of ethyl acetate. After extracting this solution with 4×20 ml of saturated NaCl solution, the ethyl acetate was evaporated and the residue recrystallized from a mixture of ethyl acetate and hexane to give 2.70g (84.9%) of light yellow crystalline product, m.p., 87-88.5°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[O:18]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCOC(=O)c1csc(N)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1csc(NC(=O)c2ccc(OC)c(OC)c2)n1
Yield: 72.9 %

Procedure:
In 100 ml of methylene chloride, 21.3 g of 2-amino-4-ethoxycarbonyl-1,3-thiazole was suspended, followed by the addition of 24.8 g of 3,4-dimethoxybenzoyl chloride, 25.3 g of triethylamine and 0.15 g of 4-dimethylaminopyridine. The resulting mixture was refluxed for 2 hours. After the reaction mixture was allowed to cool down, methylene chloride was distilled off under reduced pressure. To the residue, 1000 ml of water was added. Crystals so precipitated were collected by filtration and then recrystallized from ethanol, whereby 30.3 g of the title compound was obtained. Yield: 73%.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[C@@:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[C@@:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([CH3:29])[N:18]=[C:17]2[C:37]2[CH:38]=[N:39][C:40]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:41][C:42]=2[O:43][CH2:44][CH3:45])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([N:16]2[C@@:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[C@@:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([CH3:29])[N:18]=[C:17]2[C:37]2[CH:38]=[N:39][C:40]([C:46]([CH3:47])([CH3:49])[CH3:48])=[CH:41][C:42]=2[O:43][CH2:44][CH3:45])=[O:15])[CH2:12][CH2:13]1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A solution of {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (220 mg, 0.304 mmole, example 203) in dichloromethane (6 mL) was treated with trifluoroacetic acid (6 mL) at 0° C. and allowed to stir for 2 h before concentrated to dryness under reduced pressure. The residue was then taken up in dichloromethane (100 mL), washed with aqueous sodium carbonate (2×15 mL), water (15 mL) and concentrated to give the title compound (174 mg). HR-MS (ES, m/z) calculated for C34H42Cl2N5O2 [(M+H)+] 622.2710, observed 622.2714.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([NH2:31])[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1.0 g (4.23 mmol) of 4-chloro-7-fluoro-6-methoxyquinoline-3-carbonitrile (AM100856), 1.114 g (4.65 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine and 0.489 g (4.23 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol is heated at 120° C. for 1.5 hours, then cooled to room temperature. The resulting solid is filtered, washed with cold 2-ethoxyethanol, then ethyl acetate. After drying in vacuo, the solid is suspended in a saturated solution of sodium bicarbonate, stirred for 45 minutes and collected by filtration. The reaction product is washed with water and dried in vacuo, to provide 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile as a tan solid, mp 295-297° C.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Cl[C:25]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:26]=1[C:27]#[N:28]>>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:25]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:26]=4[C:27]#[N:28])[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Reactant: N#Cc1cc(Cl)ccc1Cl
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(c4ccc(Cl)cc4C#N)CC3)cc2)C1

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 2,5-dichlorobenzonitrile as described in example 323. This resulted in the product with the molecular weight of 452.00 (C25H30CIN5O); MS (ESI): 452 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:26][CH2:25][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:6]
Reactant: Cc1ncc(C2(CN)CCOCC2)cn1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: Cc1ncc(C2(CNC(=O)c3c(F)cccc3Cl)CCOCC2)cn1

Procedure:
From 2-chloro-6-fluorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=364.1, tR (minutes, Method F)=1.57