Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][N:4]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:30]([C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)(=[O:32])=[O:31])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1NS(=O)(=O)c1cccs1
Temperature: 25 °C

Procedure:
To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 112 mg (0.61 mmol) thiophen-2-sulfonyl chloride and 72 μL (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 95 mg (65%). HPLC-MS: M+H=472; tR=0.82 min.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:4][C:3]=2[O:2]1.[H][H]>[Pd].C1C=CC=CC=1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)=CCCC(C)=CCCc1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Product: CC(C)CCCC(C)CCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1 g. of 9-(3,4-methylenedioxyphenyl)-2,6-dimethyl-2,6-nonadiene (prepared as in Example 8) in 40 ml. of benzene was added 2.0 g. of a 5 percent palladium on carbon catalyst. Hydrogen was introduced into the reaction vessel to a pressure of 50 psig. This mixture was shaken at room temperature for 16 hours. The catalyst was removed by filtration and the benzene was evaporated under reduced pressure to yield pure 9-(3,4-methylenedioxyphenyl)-2,6-dimethylnonane (XI). The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7](Br)=[C:6](C)[C:3]=1[C:4]#[N:5].[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.[C:24](=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[NH2:1][C:2]1[C:3]([CH3:24])([C:4]#[N:5])[CH2:6][C:7]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[CH:20]=2)=[C:8]([F:11])[C:9]=1[OH:10]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1c(Br)c(F)c(O)c(N)c1C#N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C#N)CC(c2cccc(Cl)c2)=C(F)C(O)=C1N
Temperature: 100 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
2-Amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (2.0 g, 8.16 mmol), 3-chlorophenylboronic acid (2.63 g, 16.3 mmol) and cesium carbonate (5.32 g, 16.3 mmol) were dissolved in 1,4-dioxane (90 ml)/water (10 ml), and at room temperature, (tetrakistriphenylphosphine)palladium(0) (943 mg, 0.82 mmol) was added. The solution was stirred in a nitrogen steam at 100° C. for 12 hours. After cooling to room temperature, the insoluble matter was separated by filtration with washing with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated, this was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:ethyl acetate=95:5, v/v) to obtain the entitled compound (1.76 g, 78%) as a pale brown solid.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1)[C:2]([CH3:4])=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].[NH2:23][C:24](=[CH:26][C:27](=[O:29])[CH3:28])[CH3:25]>C(O)(C)C>[C:27]([C:26]1[CH:18]([C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:1]([C:5]2[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=2)=[C:2]([CH3:4])[NH:23][C:24]=1[CH3:25])(=[O:29])[CH3:28]
Reactant: CC(=O)Cc1nc(CCl)no1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)C=C(C)N
Solvent: CC(C)O
Product: CC(=O)C1=C(C)NC(C)=C(c2nc(CCl)no2)C1c1cccc([N+](=O)[O-])c1
Yield: 67.1 %

Procedure:
A stirred solution of 0.53 g of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole, 0.46 g of 3-nitrobenzaldehyde and 0.30 g of 2-amino-4-oxo-2-pentene in 4 ml of isopropyl alcohol was heated under reflux for 14 hours. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel using benzene-acetonitrile (15:1) as eluent to give 0.79 g of 5-acetyl-1,4-dihydro-2,6-dimethyl-3-(3-chloromethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]1([S:61](Cl)(=[O:63])=[O:62])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:61]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:63])=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2ccccc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and benzenesulfonyl chloride as starting materials in 44% yield. LCMS for C30H31ClN7O3S (M+H)+: m/z=604.2.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([Cl:20])=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12]>C(Cl)(Cl)Cl>[ClH:20].[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:1][CH:2]2[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]2)=[O:19])=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCN1CC(N)CN1CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(NC(=O)c2ccc([N+](=O)[O-])cc2)CN1CC
Product: Cl
Reaction time: 8 h

Procedure:
To a solution of 40.5 g (0.28 mole) of 4-amino-1,2-diethylpyrazolidine in 200 ml of chloroform was added with stirring 52 g (0.28 mole) of p-nitrobenzoyl chloride in 200 ml chloroform. The solution was allowed to stand overnight and then extracted with dilute sodium hydroxide. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized twice from isopropyl etherethyl acetate to give 73 g. (80%) of the free base.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][C@H:35]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:37]([C:47]([O:49][CH3:50])=[O:48])[CH2:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:23])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:34][C@@H:35]5[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[C@@H:37]([C:47]([O:49][CH3:50])=[O:48])[CH2:36]5)=[O:30])=[CH:32][CH:33]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CN1C(=O)OC(C)(C)C
Yield: 84.9 %

Procedure:
4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (400 mg, 0.834 mmol), (2S,4R)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate (224 mg, 0.917 mmol), PyBOP (651 mg, 1.250 mmol), and Hunig's Base (0.728 mL, 4.17 mmol) were stirred in DCM (Volume: 10 mL) for 3 days. The solvent was removed and the crude material was purified by silica gel chromatography using 60% EtOAc/hexanes to give (2R,4S)-1-tert-butyl 2-methyl 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-1,2-dicarboxylate (500 mg). 1H NMR (400 MHz, MeOD) δ ppm 1.33-1.41 (m, 4H), 1.43 (s, 9H), 2.25-2.48 (m, 2H), 3.39-3.47 (m, 1H), 3.78 (s, 3H), 3.81-3.90 (m, 1H), 4.46 (td, J=7.7, 4.8 Hz, 1H), 4.64 (qd, J=5.8, 5.6 Hz, 1H), 4.85-4.93 (m, 2H), 7.20-7.32 (m, 4H), 7.58-7.71 (m, 3H), 7.76-7.92 (m, 1H); LC-MS (Condition A), MS m/z (M++H) 706.1.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:24]([CH3:32])[CH:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:3]=1.[OH-].[Na+]>CO>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:18][C:19]([OH:21])=[O:20])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:24]([CH3:32])[CH:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:3]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)O)CC1

Procedure:
The above-titled compound was obtained by hydrolyzing the product of Example 9 with dilute aqueous sodium hydroxide in methanol; m.p. 192°-195°; after recrystallization from ethanol.
Reaction SMILES: [Mg].[C:2]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1[CH2:19][CH2:18][CH2:17]C1>>[CH:17]1([C:2]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:9])[CH2:18][CH2:19]1
Reactant: O=C(c1ccccc1)c1ccco1
Reactant: C1CCOC1
Agent: [Mg]
Product: OC(c1ccccc1)(c1ccco1)C1CC1

Procedure:
To a suspension of magnesium turnings (0.26 g, 10.5 mmol) in anhydrous tetrahydrofuran (6 ml) cyclopropyl bromide (1.28 g, 10.5 mmol) in tetrahydrofuran (5 ml) was added dropwise under nitrogen. The reaction mixture was heated at reflux for 1 h after the initial exotherm had subsided before 2-benzoylfuran (12 g, 7.0 mmol) was added as a solution in tetrahydrofuran (10 ml). The reaction mixture was worked up as described in Example 1 to give the title alcohol as an oil. T.l.c. rf=0.23 (SiO2, heptane/THF (7:3)).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[CH:16][C:17]([F:34])=[C:18]([NH:20][C:21](=[O:33])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH:41]1([C:44](Cl)=[O:45])[CH2:43][CH2:42]1.O>CN(C)C(=O)C>[C:11]([C:10]1[C:4]2[S:3][C:2]([NH:1][C:44]([CH:41]3[CH2:43][CH2:42]3)=[O:45])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([F:34])=[C:18]([NH:20][C:21](=[O:33])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[CH:19]=1)#[N:12]
Reactant: N#Cc1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(N)sc12
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of N-{5-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]-2-fluorophenyl}-2-[3-(trifluoromethyl)phenyl]acetamide (980 mg, 2.01 mmol) in N,N-dimethylacetamide (8 mL) were added pyridine (242 μL, 3.02 mmol) and cyclopropanecarbonyl chloride (255 μL, 2.81 mmol), and the mixture was stirred at room temperature for 2 hr. Cyclopropanecarbonyl chloride (255 μL, 2.81 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure. A pale-brown oil residue was crystallized from ethanol/water (1/1) to give the title compound (1.06 g, 95%) as a white powder.
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[S:14][N:13]=[C:12]([SH:15])[C:11]=2[C:16](=[O:18])[NH2:17])C=CC=CC=1.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:42][NH2:43]>CN(C=O)C.Cl.O1CCCC1>[Cl:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:42][NH:43][C:8](=[O:19])[NH:9][C:10]1[S:14][N:13]=[C:12]([S:15][CH2:20][C:21]2[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=2)[C:11]=1[C:16]([NH2:17])=[O:18]
Reactant: NCc1ccc(F)c(Cl)c1
Reactant: NC(=O)c1c(S)nsc1NC(=O)Oc1ccccc1
Reactant: Cc1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(CSc2nsc(NC(=O)NCc3ccc(F)c(Cl)c3)c2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.4 %

Procedure:
To a mixture of (4-carbamoyl-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester (0.075 g, 0.25 mmol) in 0.5 mL of DMF was added 4-methylbenzylchloride (0.036 g, 0.25 mmol), followed by N,N-diisopropylethylamine (0.033 g, 0.25 mmol). After stirring for 18 hours at ambient temperature, tetrahydrofuran (1 mL) was added, followed by 3-chloro-4-fluorobenzylamine (0.081 g, 0.51 mmol). After stirring for 24 hours at 45° C., the mixture was diluted with 1M HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by radial chromatography on silica gel eluting with ethyl acetate-hexane, affording 26 mg of 5-[3-(3-chloro-4-fluoro-benzyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylic acid amide as a colorless solid. HPLC ret. time: 4.9 minutes. 1H NMR (400 MHz, acetone-d6) δ7.95 (bs, 1H), 7.54 (dd, 1H, J=2, 7.2 Hz), 7.39 (m, 1H), 7.31-7.25 (m, 3H), 7.11 (d, 2H, J=8.0 Hz), 7.01 (bs, 2H), 4.48 (m, 4H), 2.28 (s, 3H) ppm; MS (APCI, m/z): 465 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[N:14]#[N:15].[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH:24]=[C:23]([S:30]([NH:33][C@H:34]([C:42](Cl)=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40])(=[O:32])=[O:31])[CH:22]=[CH:21]2>C(Cl)(Cl)Cl>[N:14]#[N:15].[C:1]([O:5][C:6](=[O:13])[CH2:7][N:8]([C:42](=[O:43])[C@H:34]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41])[NH:33][S:30]([C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:24]=1)(=[O:32])=[O:31])[CH2:9][CH2:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCNCC(=O)OC(C)(C)C
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Agent: N#N
Solvent: ClC(Cl)Cl
Product: CCCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Reaction time: 1 h
Yield: 82 %

Procedure:
To a stirred solution of 2.64 g of N-butylglycine tert-butyl ester in 20 ml of chloroform was carefully added N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was allowed to stand at room temperature for one hour. At the end of this period, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness. The residue was triturated with a small amount of water to give a crystalline material. This was collected by filtration and recrystallized from ethanol-ethyl ether to give 2.28 g (82 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester, M.P. 164°-166° C, I.R. (KBr): 3,390, 3,165, 1,735, 1,370 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11])=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH:18]=O>C(O)C>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])/[CH:18]=[N:13]/[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: NNC(=O)CNc1ccc(Cl)cc1
Solvent: CCO
Product: O=C(CNc1ccc(Cl)cc1)N/N=C/c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 65.8 %

Procedure:
2-(4-Chlorophenylamino)acetohydrazide (B) (101 mg, 0.51 mmol) and 3-bromo-4-fluorobenzaldehyde (104 mg, 0.51 mmol) were refluxed in ethanol (3 mL) for 15 hours. After cooling to room temperature the precipitate was collected by filtration, washed with ethanol (20 mL) and water (20 mL). Drying in vacuo yielded the title compound (129 mg, 66%) as a colorless powder. 1H NMR δ (ppm) (DMSO-d6): 3.84 and 4.28 (2 H, two d), 6.01 and 6.25 (1 H, two br s), 6.62-6.69 (2 H, m), 7.12-7.17 (2H, m), 7.47-7.51 (1 H, m), 7.77-7.83 (1 H, m), 8.01 and 8.25 (1 H, two s), 8.05-8.12 (1H, m), 11.63 (1 H, two s). LCMS (10 cm_apci_formic) Rt 3.85 min; m/z 384/386/388 [M+H].
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]#[N:15])[CH2:9]1)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]#[N:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#C[C@H]1CCC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 142.6 %

Procedure:
In a 25 mL round-bottomed flask, cis-(3-cyano-cyclohexyl)-carbamic acid tert-butyl ester (212 mg, 0.945 mmol) was combined with dichloromethane (3 ml) to give a colorless solution. Trifluoroacetic acid (0.9 mL, 11.7 mmol) was added to give a yellow solution which was stirred at room temperature for 1.5 h. The reaction mixture was then concentrated under reduced pressure. The residue was azeotroped with toluene to afford 321 mg of cis-3-aminocyclohexanecarbonitrile trifluoroacetate as a crude solid that was taken to the next step without purification. 1H NMR (300 MHz, DMSO-d6) δ: 7.96 (br. s., 3H), 2.93-3.14 (m, 1H), 2.87 (tt, J=12.2, 3.5 Hz, 1H), 2.22 (d, J=12.1 Hz, 1H), 1.96 (d, J=10.2 Hz, 1H), 1.87 (d, J=11.3 Hz, 1H), 1.68-1.81 (m, 1H), 1.49 (q, J=12.1 Hz, 1H), 1.18-1.41 (m, 3H).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.N[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=[O:31].CC[N:34](C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:34][CH:27]2[CH2:28][CH2:29][CH2:30][NH:25][C:26]2=[O:31])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: NN1CCCCC1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCCNC1=O
Temperature: 100 °C
Yield: 33 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 42 mg, 0.142 mmol), rac-aminopiperidin-2-one hydrochloride (42.7 mg, 0.283 mmol, Matrix Scientific, Inc., Columbia, S.C.), and DIPEA (123 μl, 0.709 mmol), heating at 100° C. for 1.5 h. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) and silica gel (100% DCM to 10% MeOH/DCM) provided rac-2-(2-methyl-3-((2-oxopiperidin-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-2.01 (m, 3H) 2.27-2.37 (m, 1H) 2.57 (s, 3H) 2.83-2.91 (m, 2H) 3.21-3.29 (m, 2H) 3.45 (td, J=6.94, 2.35 Hz, 2H) 4.63-4.72 (m, 1H) 6.94 (s, 1H) 7.05-7.13 (m, 2H) 7.36 (t, J=7.82 Hz, 1H) 7.60 (dd, J=8.02, 1.17 Hz, 1H) 7.82-7.89 (m, 2H) 11.85 (br. s., 1H). MS (ESI, pos. ion) m/z: 391.1 (M+1).
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[CH2:3][CH2:2]1.[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19].[Na].C[OH:25]>>[CH:1]1([CH2:4][C:5](=[O:25])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[CH:21]([N+:18]([O-:20])=[O:19])[CH3:22])[CH2:3][CH2:2]1
Reactant: CO
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc(C=CC(=O)C2CC2)cc1OC
Agent: [Na]
Product: COc1ccc(C(C(=O)CC2CC2)C(C)[N+](=O)[O-])cc1OC

Procedure:
The procedure of Example IX using 21 g of 1-cyclopropyl-3-(3',4'-dimethoxyphenyl)prop-2-en-1-one, 8 ml of nitroethane and 1.2 g of sodium in 80 ml of methanol gives 16 g of 1-cyclopropyl-3-(3',4'-dimethoxyphenyl)-4-nitropentanone, which is used in the crude state for the remainder of the operations.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[CH2:18]([NH:21][S:22]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)(=[O:24])=[O:23])[CH:19]=[CH2:20]>>[CH2:18]([NH:21][S:22]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:30][CH:31]=1)(=[O:24])=[O:23])[CH:19]=[CH2:20]
Reactant: C=CCNS(=O)(=O)Cc1ccc(N)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: C=CCNS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and N-allyl-4-aminophenylmethane sulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 11.1 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.5 (q, 4H), 7.3 (t, 1H), 7.1 (d, 1H), 5.8 (m, 1H), 5.2 (d, 1H), 5.1 (d, 1H), 4.4 (s, 2H), 3.6 (t, 2H); APCI-MS m/z 427 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](OC(C)(C)C)=[O:8])=[C:2]1[NH:14][C:15]([O:17]C(C)(C)C)=O.C(OCC)(=O)C(OCC)=O>C(O)(=O)C>[NH:6]1[C:7](=[O:8])[C:15](=[O:17])[NH:14][C:2]2[S:1][CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)(C)OC(=O)Nc1ccsc1NC(=O)OC(C)(C)C
Solvent: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: O=c1[nH]c2ccsc2[nH]c1=O
Yield: 78.1 %

Procedure:
A mixture of di-t-butyl thiophene-2,3-dicarbamate (1.53 g, 4.87 mmol), diethyl oxalate (15 ml) and acetic acid (15 ml) was refluxed for 48 hours. The precipitate was filtered off, washed with water and dried to yield 0.64 g (78%) of the title compound. M.p. >340° C. 1H-NMR (DMSO-d6, δ): 6.74 (d, 1H), 7.13 (d, 1H), 12.28 (s, 1H).