Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C(Cl)=CC(C2NC(C3C=CC(Cl)=CC=3)(C)C(C3C=CC(Cl)=CC=3)(C)N=2)=[C:7]([O:33]CC)C=1)(C)(C)C.Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:41])=[O:40]>>[CH3:38][S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][N:48]([CH:7]=[O:33])[CH2:47][CH2:46]1)(=[O:40])=[O:41]
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CS(=O)(=O)CCCN1CCN(C=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the racemic rac-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone. Chiral separation of the enantiomers by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C38H48N4O4SCl3 [(M+H)+] 761.2457, observed 761.2460.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:32])[CH2:9][N:10]2[C:15]3=[N:16][C:17]([N:21]4[CH2:26][C@@H:25]5[CH2:27][C@H:22]4[CH2:23][O:24]5)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][C@H:11]2[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>C(O)C>[OH:34][CH2:33][CH2:35][NH:36][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:32])[CH2:9][N:10]2[C:15]3=[N:16][C:17]([N:21]4[CH2:26][C@@H:25]5[CH2:27][C@H:22]4[CH2:23][O:24]5)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][C@H:11]2[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccc(Cl)nc1
Solvent: CCO
Product: O=C(CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccc(NCCO)nc1
Temperature: 130 °C
Yield: 49.1 %

Procedure:
A mixture of 0.50 mL of ethanol, 33 mg (0.070 mmol) of (8S)-9-[2-(6-chloropyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 21.41 μl (0.352 mmol) of ethanolamine is heated in a Biotage microwave reactor at 130° C. for 30 minutes. The reaction mixture is evaporated to dryness and the residue is then taken up in 10 mL of water. The precipitate is filtered off and then dried under vacuum. 17 mg of (8S)-9-{2-[6-(2-hydroxyethylamino)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH:54](O[Na])([CH3:56])[CH3:55].[Cl-].[NH4+]>C(O)(C)C.C(N(CC)CC)C.ClCCl>[CH:54]([O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])([CH3:56])[CH3:55]
Reactant: CC(C)O[Na]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Reaction time: 0.02 h
Yield: 57.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.3 g, 0.54 mmol) was added into a 50 mL reaction flask, followed by addition of 10 mL of dichloromethane, 2 mL of isopropanol and 0.3 mL of triethylamine. After stirring for 1 minutes, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.277 g, 1.09 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours, and then 10 mL of isopropanol and isopropoxysodium (0.177 g, 2.16 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. 10 mL of saturated ammonium chloride was added to the reaction mixture, and white precipitates were formed. The precipitates were filtered through a pad of silica gel, and 50 mL of water was added to the filtrate. The filtrate was extracted with ethyl acetate (25 mL×5), and the combined organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid isopropyl ester 35a (0.185 g, yield 57.8%) as a white solid.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C=Cc1ccc2nnn(O)c2c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=Cc1ccc2nnn(OS(=O)(=O)c3ccc(Cl)cc3)c2c1
Temperature: 10 °C
Yield: 83.4 %

Procedure:
In benzene (100 ml) are dissolved 1-hydroxy-6-vinyl-1,2,3-benzotriazole (8.0 g) and triethylamine (5 g) under stirring and thereto is added dropwise a solution of p-chlorobenzenesulfonyl chloride (10.6 g) in benzene (100 ml) under cooling to 10° C. The mixture is stirred at room temperature for 3 hours. The reaction mixture is poured onto ice-water (200 ml) and then extracted with ethyl acetate (150 ml, twice). The combined extracts are washed with water, dried over anhydrous magnesium sulfate, treated with charcoal and then concentrated till about 30 ml. To the mixture is added n-hexane and the mixture is allowed to stand at a cooled place. The precipitated crystals are separated by filtration to give 1-(p-chlorobenzenesulfonyloxy)6-vinyl-1,2,3-benzotriazole (13.9 g), melting point: 125° C. The filtrate is further concentrated and the resulting residue is dissolved in ethyl acetate (10 ml). To the solution is added n-hexane and the mixture is allowed to stand at a cooled place to give additionally the desired product (1.0 g).
Reaction SMILES: [CH:1]([C@:3]1([CH3:27])[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O.[CH2:28]([O:35][C:36]([CH:38]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([O:35][C:36](/[CH:38]=[CH:1]/[C@:3]1([CH3:27])[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@]1(/C=C/C(=O)OCc2ccccc2)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
763 mg (2.0 mmol) of benzhydryl (2S,3R,5R)-3-formyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 15 ml of THF under argon, treated with 821 mg (2.0 mmol) of benzyloxycarbonylmethylene-triphenylphosphorane and the orange solution was stirred at 50° C. for 2 hours. It was left to cool to room temperature, the solvent was removed on a rotary evaporator and the red-brown oil was chromatographed over silica gel (particle size 0.040-0.063 mm) with ethyl acetate:hexane (9:16) as the eluent.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][OH:20])[CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][O:20][C:22]3[CH:54]=[CH:53][C:25]([CH2:26][CH:27]4[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]4=[O:52])=[CH:24][CH:23]=3)[CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=NOCCO)c1ccc(Sc2ccccc2)cc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(Sc2ccccc2)cc1
Yield: 88.5 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 862 mg of 2-[1-(4-phenylthiophenyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 36), 1.40 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 866 mg of triphenylphosphine and 549 mg of diethyl azodicarboxylate, 1.95 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: O[CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:25])[CH:24]=2)[CH:3]1[CH3:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:51]I>C1(C)C=CC=CC=1>[I:51][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:25])[CH:24]=2)[CH:3]1[CH3:26]
Reactant: CC1C(O)C2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1C1=CC(=O)OC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1C(I)C2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1C1=CC(=O)OC1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a solution of the compound of step C (370 mg, 1.01 mmol) in toluene (20 mL) at rt was added PPh3 (397 mg, 1.515 mmol), imidazole (137 mg, 2.02 mmol), and I2 (384 mg, 1.515 mmol). The mixture was stirred for 10 h at 100° C., and quenched with NaHCO3 aqueous solution. The organic layer was diluted with DCM, separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried (MgSO4) and purified by column chromatography (0-100% EtOAc/hex) to give the title compound. LC/MS: [(M+1-56)]+=421
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH3:12])[C:5]=1[OH:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH3:12])[C:5]=1[OH:13]
Reactant: CCCc1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Product: CCCc1cccc(N)c1O
Yield: 90.2 %

Procedure:
To a solution of 2-nitro-6-n-propylphenol (2 g, 11.0 mmol) in methanol (100 mL) was added 10% Pd/C (200 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/CH2CH2) gave the desired product (1.50 g, 80.2%). 1H NMR (CD3OD): d 6.65 (m, 2H), 6.55 (t, 1H), 2.58 (t, 2H), 1.61 (m, 2H), 0.96 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10](N2CCOCC2)=[O:11])[CH:7]=1.[CH:22]([Li])([CH3:24])[CH3:23]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10](=[O:11])[CH:22]([CH3:24])[CH3:23])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Reactant: [Li]C(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.45 g) in THF (2 mL) stirred under argon and cooled on dry ice/acetone was added isopropyl lithium (0.7M in pentane, 3 mL) over 10 minutes. The mixture was stirred for 20 minutes and quenched with EtOH (0.3 mL). The mixture was warmed to room temperature and water 1 mL was added. The organic phase was separated, washed, dried, filtered, and evaporated. The residue was fractionated over a short column of silica gel (eluent: hexanes-methylene chloride (1:1)) to give the product as an oil (0.40 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][C:2]1=[O:11].[N:12]([O-])=[O:13].[Na+]>Cl.O>[N:12]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:2](=[O:11])[CH2:3]1)=[O:13]
Reactant: O=C1CNc2ccccc2N1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CC(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66.8 %

Procedure:
3,4-Dihydro-1H-quinoxalin-2-one (500 mg, 3.378 mmol) was dissolved in 3N HCl (10 mL) and stirred for 5 min. at 0° C. A solution of sodium nitrite (256 mg, 3.716 mmol) in water (2 mL) was added at 0° C., and the reaction mixture was stirred for 2 h at RT. After completion of reaction, water was added and the mixture extracted twice with DCM (100 mL). The combined organic layers were washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 400 mg of 3,4-dihydro-4-nitrosoquinoxalin-2(1H)-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: Clc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
52 mg tetrakis(triphenylphosphine) palladium was added to 100 mg 2-chloropyridine, 327 mg 4-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester and 0.88 mL 2 mol/L sodiumcarbonate in 2 mL dioxane. The reaction was stirred for 15 min. at 140° C. in a microwave. Water was added and the reaction was extracted with DCM. The organic layer was dried and evaporated. The residue was purified by HPLC to yield 116 mg of the desired product. Rt: 1.03 min (method L), (M+H)+: 261
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:14](/[N+:11]([O-:13])=[O:12])\[CH3:15])=[C:4]([F:10])[CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1F
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C/C(=C\c1ccc(Cl)cc1F)[N+](=O)[O-]
Temperature: 25 °C
Yield: 76.4 %

Procedure:
4-Chloro-2-fluorobenzaldehyde (10 g, 63.1 mmol), nitroethane (54.6 mL, 757 mmol) and piperidine (1.869 mL, 18.92 mmol) were dissolved in toluene (150 mL) and refluxed under Dean Stark conditions overnight. The reaction mixture was cooled to room temperature and the solvents were evaporated. The crude product was purified by column chromatography (silica, heptane/EtOAc 98:2) to give the desired product (10.4 g, 76%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>O1CCOCC1.O>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:1][C:2]2([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: NC1(C(=O)O)CCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC2(C(=O)O)CCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-aminocyclopentane-1-carboxylic acid (6.0 grams, 46.5 mmole) and triethylamine (14 mL, 100 mmole) in dioxane (90 mL) and water (90 mL) was added 4methoxybenzenesulfonyl chloride (10.6 grams, 51.3 mmole). The resulting mixture was stirred at room temperature for 4 hours, acidified with aqueous 1N hydrochloric acid solution, and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over magnesium sulfate and concentrated to leave a tan solid which was triturated with chloroform to afford 1-(4-methoxybenzenesulfonylamino)-cyclopentane-1 carboxylic acid as a white solid, 5.42 grams (39%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C1CCNC1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCN4CCCC4)c(F)cc(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
709 mg (1.35 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 30 mL of dimethylformamide under argon atmosphere, 1.14 mL (13.5 mmol) of pyrrolidine and 1.86 g (13.5 mmol) of potassium carbonate were added and the mixture was stirred at 50° C. for 8 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:9:1) to give 431 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-[3-(pyrrolidin-1-yl)propylamino]-4H-1-benzopyran-4-one (yield: 64%).
Reaction SMILES: BrC1C=C2C(=CC=1[Cl:12])C=NC=C2.[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[CH:21]2)=[CH:16][C:15]=1[S:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1.C(OC(N1CCCC(O)C1)=O)(C)(C)C>>[ClH:12].[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[CH:21]2)=[CH:16][C:15]=1[S:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1
Reactant: Clc1cc2cnccc2cc1Br
Agent: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: Clc1cc2cnccc2cc1SC1CCCNC1
Product: Cl

Procedure:
Starting from 6-Fluoro-7-chloroisoquinoline (263) and 3-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Rac)-7-Chloro-6-(piperidin-3-ylsulfanyl)-isoquinoline could be obtained as the hydrochloride as described for compound (268). Rt=0.80 min (Method B). Detected mass: 279.1/281.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: NC(=O)c1cc(F)ccc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(F)cc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 8.8 mmol) and 2-amino-5-fluorobenzamide (4.0 g, 26 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-5-fluorobenzamide was isolated as a white solid (3.05 g, 76% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.68 (d, J=4.03 Hz, 1 H), 7.42-7.50 (m, 3 H), 7.65 (dd, J=9.51, 3.11 Hz, 1 H), 7.72 (d, J=3.84 Hz, 1 H), 7.83 (s, 1 H), 7.97 (dt, J=8.65, 1.90 Hz, 2 H), 8.26 (s, 1 H), 8.30 (dd, J=9.15, 5.12 Hz, 1 H), 11.81 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15](SC)=[N:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:6]=1)[CH3:3].[CH2:23]([NH2:25])[CH3:24]>>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:25][CH2:23][CH2:24][S:11][CH2:10][C:8]2[O:9][CH:5]=[CH:6][CH:7]=2)=[N:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CCN
Reactant: CSC(=NS(C)(=O)=O)NCCSCc1ccc(CN(C)C)o1
Product: CN(C)Cc1ccc(CSCCNC(=NS(C)(=O)=O)NCCSCc2ccco2)o1
Yield: 184.5 %

Procedure:
A mixture of N-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]-N'-methylsulphonylcarbamimidothioic acid, methyl ester (1.82 g) and 2-(2-furanylmethyl)thio]ethanamine (0.785 g) was heated at 120° for 5 hours. The reaction mixture was chromatographed (silica/ethyl acetate-methanol 3:1) and the appropriate eluate evaporated to dryness to give the title compound (2.18 g), as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[CH2:3][CH2:2]1.[OH:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH:21]3[NH:28][CH3:29])[CH2:19]1)[CH2:25]2>>[OH:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH:21]3[N:28]([CH3:29])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([O:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:9]=3)[CH2:19]1)[CH2:25]2
Reactant: O=C(O)c1cccc(OC2CCOCC2)c1
Reactant: CNC1C2CC3CC1CC(O)(C3)C2
Product: CN(C(=O)c1cccc(OC2CCOCC2)c1)C1C2CC3CC1CC(O)(C3)C2

Procedure:
Prepared from 3-(tetrahydro-pyran-4-yloxy)-benzoic acid and 1-hydroxy-4-methylaminoadamantane. LC-MS (m/z): 387 (M+2).