Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:12]([CH:14]=[CH:15][C:16](O)=[O:17])=[O:13].ClC(OCC)=O.N>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:12](=[O:13])[CH:14]=[CH:15][C:16]([NH2:3])=[O:17])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=C(O)C=CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: NC(=O)C=CC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
28 ml of triethylamine was dissoved in 600 ml of cloroform, then 49 g of 3-(3,4-dichlorobenzoyl)acrylic acid was added. The resulting solution was cooled to 0° C, and 42 g of ethyl chloroformate was added. The mixture was warmed to 20° C, stirred for one hour, cooled to 0° C and then held there while gaseous ammonia was passed into the solution until no further heat of reaction was noted. A precipitate that formed was collected, washed with water and then with acetone to give 4-(3,4-dichlorophenyl)-4-oxo-2-butenamide (4A), as a white solid, m.p.: 208° C (with decomposition).
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[SH:10][CH2:11][C:12]1[NH:13][C:14]([CH3:37])=[C:15]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[O-]CC.[Na+].CC(O)=O>C(O)C>[N:2]1([CH2:7][CH2:8][S:10][CH2:11][C:12]2[NH:13][C:14]([CH3:37])=[C:15]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: ClCCN1CCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(CSCCN2CCCC2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 41.8 %

Procedure:
A solution of 2-(pyrrolidin-1-yl)-1-chloroethane hydrochloride (2.8 g), 2-mercaptomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine (5.4 g) and sodium ethoxide (2 g) in ethanol (70 ml) is heated to the reflux temperature for 6 hours, then it is neutralized with AcOH and evaporated under reduced pressure. The residue, after the usual work-up, is purified by column-chromatography (SiO2 ; 210 g; eluent AcOH/MeOH 99/1) to give 2.8 g of 2-[2-(pyrrolidin-1-yl)ethylthio]methyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine, as an oil, that upon treatment with fumaric acid gives the corresponding salt, m.p. 192°-194° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:3]=1.[O:23]=[C:24]([C:28]1[N:36]2[C:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)=[CH:30][C:29]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:25](=[O:26])[C:24](=[O:23])[C:28]4[N:36]5[C:31]([CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:30][C:29]=4[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:20][CH:21]=3)[CH2:11][CH2:10]2)[CH:3]=1
Reactant: Cc1cc(C)nc(N2CCCN(c3ccc(N)cc3)CC2)c1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)nc(N2CCCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenyl amine (prepared as described in Reference Example 90, 800 mg, 2.70 mmol) in DCM (30 mL) was added oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (prepared as described in Reference Example 21, 930 mg, 3.24 mmol) and triethylamine (0.75 mL, 5.4 mmol). The mixture was stirred for 2 h at room temperature then concentrated in vacuo to give a residue which was purified by flash chromatography on silica gel (60-120 mesh) eluting with 30% ethyl acetate/n-hexane to afford N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (500 mg, 35%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([CH3:44])=[C:6]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:7]([C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=2[O:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]2C(=O)C3=CC=CC=C3C2=O)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].O.NN>C(O)C>[NH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:15]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[CH:7]1[C:6]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:5]([CH3:44])[NH:4][C:3]([CH2:1][CH3:2])=[C:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1=C(C)NC(CC)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1OCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C(C)NC(CC)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Yield: 65.7 %

Procedure:
A solution of 12.4 g of diethyl 2-ethyl-4-[2-(4-phthalimidobutoxy)-5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate and 10.4 g of hydrazine monohydrate in 270 ml of 95% ethanol (water: 5%) was refluxed under heating for 10 hours. After cooling the reaction solution, the solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Crude crystals thus obtained were recrystallized from chloroform-ether to give 6.4 g of diethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2-ethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:10]=1)[C:5]([OH:7])=O.FC1C=C(C=C(C(F)(F)F)C=1)[C:18]([N:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[O:35][CH3:36])C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:10]=1)[C:5]([N:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[O:35][CH3:36])[CH3:18])=[O:7]
Reactant: O=C(O)c1cc(Cl)cc(C2CC2)c1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(C2CC2)c1

Procedure:
The title compound was prepared in analogy to example 90, from 3-chloro-5-cyclopropylbenzoic acid and 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (0.18 g, 775 μmol, example 129, intermediate) after a reaction time of 41 hours at room temperature. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.012 g; 3%). MS (ESI): m/z=411.13 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][C:7]=1[CH:15]([NH:21][C:22]1[CH:27]=[CH:26][C:25](/[C:28](=[N:31]/[H])/[NH:29]O)=[CH:24][CH:23]=1)[C:16]([O:18][CH2:19]C)=[O:17])(=[O:3])[NH2:2]>CO.C(O)(=O)C.[Ni]>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][CH:15]([C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:1](=[O:3])[NH2:2])[C:16]([O:18][CH3:19])=[O:17])=[CH:27][CH:26]=1)(=[NH:29])[NH2:31]
Reactant: [H]/N=C(\NO)c1ccc(NC(C(=O)OCC)c2cc(OCC)ccc2OCC(N)=O)cc1
Agent: [Ni]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1ccc(OCC(N)=O)c(C(Nc2ccc(C(=N)N)cc2)C(=O)OC)c1
Yield: 93.4 %

Procedure:
305 mg of ethyl (Z)-(RS)-(2-carbamoylmethoxy-5-ethoxy-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetate were treated in 8 ml of methanol-acetic acid (1:1) with Raney-nickel and stirred under hydrogen. The reaction mixture was filtered, evaporated in a vacuum and, for purification, the residue was triturated in acetonitrile. There were obtained 265 mg of methyl (RS)-(4-carbamimidoyl-phenylamino)-(2-carbamoylmethoxy-5-ethoxyphenyl)-acetate; m.p. 200° C. (dec.), MS: 401 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-:3])=[O:2].[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[N+:17]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:13]([Cl:14])[CH:12]=[C:11]2[C:6]=1[NH:7][C:8](=[O:16])[C:9](=[O:15])[NH:10]2)([O-:19])=[O:18]
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c([N+](=O)[O-])c2[nH]c1=O
Temperature: 4 °C
Reaction time: 48 h
Yield: 70.5 %

Procedure:
To a solution of 6-nitro-7-chloro-1,4-dihydro-2,3-quinoxalinedione (120 mg, 0.50 mmol) in concentrated H2SO4 (1.0 mL) was added KNO3 (61 mg, 0.60 mmol, Baker). The mixture was stirred at 4° C. for 2 days, then ice (2 g) was added. The precipitate was collected by filtration and the solid was dissolved in 1N NaOH (5 mL) and filtered. The filtrate was acidified to pH=2 with 4N HCl (~1.2 mL) to give a yellow precipitate, which was collected by filtration and was washed with water (2×1 mL), then was dried at 50° C. for 4 h, affording crude title compound (101 mg, 70%) as a yellow 1.5 powder. The crude compound (100 mg) was dissolved into acetone (2 mL) and the insoluble material was removed by centrifugation. Water (1 mL) was added to the clear solution of acetone and the resultant solution was allowed to stand at 4° C. overnight to give purer compound. Recrystallization from acetone/water again gave pure title compound (55 mg). Mp: 298°-300° C. (dec.); IR (KBr, cm-1): 3434, 3295, 3111, 2920, 1716, 1571. 1H NMR (DMSO-d6): δ12.560 (s, 1H), 12.421 (s, 1H), 7.442 (s, 1H). HRMS; calcd for C8H3ClN4O6 (M+) m/z: 285.9740, found: 285.9741.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[C:17](O)(=[O:19])C>C=O>[CH2:1]([N:5]1[C:9]([CH2:17][OH:19])=[C:8]([CH3:10])[N:7]=[C:6]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(C)nc1-c1ccccc1
Reactant: CC(=O)O
Agent: C=O
Product: CCCCn1c(-c2ccccc2)nc(C)c1CO

Procedure:
A solution of 112 (1 g) in acetic acid (10 mL) and 40% aqueous formaldehyde (2 mL) is refluxed for 14 h. The reaction is then concentrated and dried by repeated reconcentration with toluene. The residue is purified by column chromatography (10% MeOH/CHCl3). The fractions are assayed by GC and those fractions uncontaminated by the isomeric hydroxymethylimidazole combined. Concentration of the combined. fractions provides compound 113 (320 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.4-7.6 (m, 6H), 4.61 (s, 2H, CH2OH), 4.02 (t, J=7 Hz, 2H, NCH2), 2.22 (s, 3H, Me), 1.63 (m, 2H, 1.25 (m, 2H), 0.81 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:16][S:17](=[O:31])(=[O:30])[O:18][C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[Li+].[OH-].CO>O1CCCC1>[CH3:1][C:2]1[C:3]([O:16][S:17](=[O:31])(=[O:30])[O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)Oc2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cc1OS(=O)(=O)Oc1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Temperature: 55 °C
Reaction time: 8 h
Yield: 0.6 %

Procedure:
To a solution of 58 mg (0.15 mmol) of ethyl 4-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthylsulfoxy)benzoate (Compound 8) in 4.0 mL of tetrahydrofuran was added 1.0 mL of LiOH (2N aqueous solution) and 2.0 ml of MeOH. The solution was heated at 55° C. for 2 h and stirred at room temperature for 8 h. The reaction mixture was then concentrated in vacuo. The residue was diluted with brine and 10% HCl and extracted with diethyl ether (2×). The combined ether layers were dried (MgSO4), filtered, and the solvents removed in vacuo to give the title compound as a white solid (0.39 mg, 72%):
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][N:27]1[C:23]([C:2]2[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)=[CH:24][CH:25]=[N:26]1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc(C(=O)O)s1
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-2-thiophenecarboxylic acid (100 mg, 0.48 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (267 mg, 1.93 mmol), tetrakistriphenylphosphine Pd(0) (28 mg, 24 umol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (94 mg, 0.48 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (˜100 mg, quant.): LC-MS (ES) m/z=209 (M+H)+.
Reaction SMILES: CS(C)=O.[H-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.Br[CH2:18][CH2:19][CH2:20]Br>C(OCC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:15]#[N:16])[CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
Into a round-bottom flask under argon fitted with an addition funnel and thermometer was added anhydrous dimethylsulfoxide and sodium hydride (1.17 g, 48.8 mmol, 95%). Then a solution of (4-chlorophenyl)acetonitrile (A) (2.70 mL, 22.2 mmol) and 1,3-dibromopropane (2.48 mL, 24.4 mmol) in diethyl ether (15 mL) was added slowly, while maintaining the reaction temperature at 20-30° C. The reaction mixture was maintained at room temperature for overnight. The reaction mixture was carefully quenched with water (50 mL) and then extracted with hexane (3×100 mL). The organic extracts were combined, washed with water (3×75 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give 2.9 g of 1-(4-chlorophenyl)-cyclobutanecarbonitrile, B, as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 2.03-2.09 (m, 1H); 2.36-2.62 (m, 3H); 2.76-2.84 (m, 2H); 7.34 (s, 4H); 13C NMR (CDCl3, 75 MHz): δ 17.0, 34.6 (2C), 39.7,123.9, 127.1, 129.1, 133.7, 138.3.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:35]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]1[CH3:48])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:45]4[CH2:46][CH2:47][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:43]([CH3:48])[CH2:44]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(=O)OC(C)(C)C)[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (80.0 mg, 0.155 mmol) and (R)-1-boc-2-methylpiperazine (93.1 mg, 0.465 mmol) in 1,4-dioxane (2 mL) was added triethylamine (156.8 mg, 0.19 mL, 1.549 mmol). The reaction mixture was stirred at 40° C. for 4 h, at room temperature overnight, then at 40° C. for an additional 7 h. The reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C35H43ClN5O5S (M+H+): 680.3; Found: 680.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:60])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([C:47]#[N:48])[CH2:44][N:43]6[C:49](=[O:59])[CH:50]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:51]([CH3:53])[CH3:52])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(N1CC[CH2:68][C@H:64]1[C:65](O)=O)#N.COC(NC(C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:60])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([C:47]#[N:48])[CH2:44][N:43]6[C:49](=[O:59])[CH:50]([NH:54][C:55]([O:57][CH3:58])=[O:56])[C:51]6[CH:53]=[CH:68][CH:64]=[CH:65][CH:52]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: N#CN1CCC[C@H]1C(=O)O
Agent: COC(=O)NC(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1

Procedure:
Synthesized similar to [1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester, reverting the order of Suzuki coupling and reaction introduction of the amino acid moiety on the cyano proline using methoxycarbonylamino-phenyl-acetic acid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].C(O)(=O)C.[F:10][C:11]([F:27])([F:26])[C@@H:12]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:27][C:11]([F:10])([F:26])[C@@H:12]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:1][CH2:2][C@H:3]([OH:5])[CH3:4])=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)N[C@@H](c1ccc(C=O)cc1)C(F)(F)F
Reactant: C[C@@H](O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H](O)CNCc1ccc([C@H](NS(C)(=O)=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Dissolve (2R)-1-aminopropan-2-ol (0.4 g, 5.33 mmol) in DCM (10.6 mL); then acetic acid (366.2 uL, 6.39 mmol) and N-[(1S)-2,2,2-trifluoro-1-(4-formylphenyl)-ethyl]-methanesulfonamide (1.65 g, 5.86 mmol). Stir the resulting mixture at ambient temperature for 2 hours; then add sodium triacetoxyborohydride (2.82 g, 13.31 mmol); and stir at ambient temperature overnight. Add MeOH (1 mL) and evaporate a portion of the solvent under reduced pressure. Purify via SCX chromatography eluting with 2M NH3/MeOH. Concentrate the appropriate fractions under reduced pressure to give the title compound (1.7 g, 93.8%). MS (m/z): 341 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[O:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>C(O)(=O)C>[O:1]=[C:2]1[N:6]([C:16](=[O:18])[CH3:17])[N:5]=[C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]nc(-c2nc3ccccc3o2)o1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)n1nc(-c2nc3ccccc3o2)oc1=O

Procedure:
5.0 g of 2-(2-oxo-3H-1,3,4-oxadiazole-5-yl)benzoxazole in 50 ml of acetic acid containing 5 ml of acetic anhydride was heated for 1 hour at 100°. The mixture was poured into water and the crystalline product filtered. Recrystallization from acetonitrile gave mp. of 231°-232°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1.CO[CH:16]=[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[C:20](=[O:28])[NH:19][C:18]1=[O:29]>CN(C)C=O>[OH:9][C:7]1[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=[C:3]([CH2:2][NH:1][CH:16]=[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=3)[C:20](=[O:28])[NH:19][C:18]2=[O:29])[CH:8]=1
Reactant: CCCOc1cnc(CN)cc1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: CCCOc1cnc(CNC=C2C(=O)NC(=O)c3ccc(Br)cc32)cc1O

Procedure:
A mixture of 2-aminomethyl-5-propoxy-pyridin-4-ol (137 mg, 0.75 mmole) in 10 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-bromo-4H-isoquinoline-1,3-dione (212 mg, 0.75 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give a beige solid, 303 mg, (93%); MS (ES+): m/z 432.0 (M+H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.Cl.[CH3:16][O:17][NH2:18]>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([NH:18][O:17][CH3:16])=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Reactant: CON
Agent: Cl
Product: CONC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Yield: 53.5 %

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (502 mg; 2 mmol) and O-methylhydroxylamine hydrochloride (300 mg) and with the use of the same procedure as in example 21, 280 mg (57%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 11.35 (s, 1H, NH), 11.28 (s, 1H, NH), 7.78 (d, 1H, H-8), 7.63 (dd, 2H, H-6 and H-5), 3.80 (s, 3H, CH3); 13C-NMR (DMSO-d6) ppm; 151.19, 132.79, 131.26, 127.10, 123.00, 120.83, 118.78, 63.25.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1>C(Cl)Cl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:39])=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (63 μL, 0.36 mmol) in DCM (2 mL) was added 4-fluorophenylacetyl chloride (62 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 give the title compound as a white oil. MS (ESI, positive ion) m/z: 414 (M+H).