Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[C:21](Cl)=[O:22]>N1C=CC=CC=1>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[C:21]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])=[O:22]
Reactant: COC(=O)c1sccc1N
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NC(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-amino-2-thiophenecarboxylate (0.82 g, 5.2 mmol) and 2-quinoxalinecarbonyl chloride at 0° C. was added pyridine (1 mL) dropwise. The resulting solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed with saturated NH4Cl, and NaHCO3. The organic layer was the dried and concentrated in vacuo. The crude product was used directly in the next step without further purification.
Reaction SMILES: ClCCl.FC(F)(F)C(O)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:23][CH:24]2[CH:29]([CH2:30][C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH2:28][O:27][C:25]2=[O:26])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]>C(OCC)(=O)C>[CH3:42][O:41][C:33]1[C:34]([O:39][CH3:40])=[C:35]([O:37][CH3:38])[C:36]2[C:14]3[C:13]([O:12][CH3:11])=[C:18]([O:19][CH3:20])[C:17]([O:21][CH3:22])=[CH:16][C:15]=3[CH2:23][CH:24]3[C:25](=[O:26])[O:27][CH2:28][CH:29]3[CH2:30][C:31]=2[CH:32]=1
Reactant: COc1cc(CC2COC(=O)C2Cc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(c(OC)c1OC)-c1c(cc(OC)c(OC)c1OC)CC1C(=O)OCC1C2
Temperature: 25 °C
Reaction time: 19 h
Yield: 57.3 %

Procedure:
Dissolved in a mixture consisting of 0.5 ml of dichloromethane and 0.05 ml of trifluoroacetic acid were 50 mg (0.112 mmol) of 2,3-bis[1-(3,4,5-trimethoxyphenyl)methyl]butanolide. The solution was added with 150 mg (0.32 mmol) of ferric perchlorate, followed by stirring at room temperature for 19 hours. The reaction mixture was dissolved in 10 ml of ethyl acetate. The resulting solution was washed successively with 2N-HCl, water and saturated NaHCO3. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby colorless oil was obtained. The oil was purified by thinlayer chromatography (TLC) (silica gel: "MERCK #5744", eluent: 1:3 mixed solvent of acetone and hexane), whereby 28.5 mg of the title compound were obtained as a colorless solid (yield: 57%).
Reaction SMILES: [CH2:1]([C:4]1([CH2:10][O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH2:19].[OH-].[Na+].OO>O1CCCC1>[CH2:13]([Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:11][CH2:10][C:4]1([CH2:1][CH2:2][CH2:3][OH:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH3:14]
Reactant: O
Reactant: C=CCC1(CO[Si](CC)(CC)CC)CCCCC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OCC1(CCCO)CCCCC1
Reaction time: 2 h

Procedure:
To a solution of [1-(allylcyclohexyl)methoxy]triethylsilane (1.70 g) in tetrahydrofuran (35 mL) were added a 2M borane-methyl sulfide complex solution in tetrahydrofuran (6.48 mL, 12.96 mmol) under ice cooling. The solution was stirred under ice cooling for 2 hours. To this were then added water, a 3N aqueous sodium hydroxide solution (6.5 mL) and 30% hydrogen peroxide (6.5 mL). The solution was stirred at room temperature for 16 hours. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=7:3) to give the title compound (810 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]([C:16]2[CH:20]=[CH:19][O:18][C:17]=2[CH3:21])=[O:15])[CH:9]=[CH:10][C:11]=1[Cl:12])(=O)C.[OH-].[K+]>O>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:14]([C:16]2[CH:20]=[CH:19][O:18][C:17]=2[CH3:21])=[O:15])=[CH:7][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1cc(NC(=O)c2ccoc2C)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1occc1C(=O)Nc1ccc(Cl)c(CO)c1
Temperature: 70 °C
Yield: 94.5 %

Procedure:
A solution of 29 g of the N-(3-acetoxymethyl-4-chlorophenyl)-2-methyl-3-furancarboxamide prepared in Step 4 above and 14.5 g potassium hydroxide in 110 mL water, was prepared. The solution was then heated at 70° C. for 16 hours and then acidified with 2N hydrochloric. The resulting solid was collected, washed with water, and dried, producing 23.65 g of N-(4-chloro-3-hydroxymethylphenyl)-2-methyl-3-furancarboxamide as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=2[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(N1CC2C=CC=CC=2OCC1)C1C=CC=CC=1>>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CN(Cc1ccccc1)C(=O)CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc2c(c1)CN(Cc1ccccc1)CCO2

Procedure:
This compound was prepared from 5.7 g of 4-benzyl-7-methoxy-4,5-dihydro-benzo[f][1,4]-oxazepin-3-one and 2.3 g of lithium aluminum hydride using the procedure described for 64d. Yield: 6.1 g (oil), EI-MS: 269 (M+).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:9]2[C@H:4]([NH:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.[Cl:17][C:18]1[C:19]([C:25]#[N:26])=[N:20][CH:21]=[C:22](Cl)[N:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:17][C:18]1[N:23]=[C:22]([N:5]2[CH2:6][CH2:7][CH2:8][C@H:9]3[N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2][CH2:3][C@@H:4]23)[CH:21]=[N:20][C:19]=1[C:25]#[N:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2NCCC[C@H]21
Reactant: N#Cc1ncc(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H]1CCCN2c1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.9 %

Procedure:
Commercial (3aR,7aR)-tert-butyl octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (416, CAS: 1251010-63-5, 476 mg, 2.1 mmol) was dissolved in 15 mL DMF. To it were added 3,5-dichloropyrazine-2-carbonitrile (340 mg, 1.9 mmol) and DIEA (500 μL, 2.9 mmol). The mixture was stirred at RT for 3.5 hours, diluted with 100 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 3% MeOH in DCM to isolate (3aR,7aR)-tert-butyl 4-(6-chloro-5-cyanopyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (417, 670 mg, 88%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:7]([C:14]([O:16]CC)=[CH2:15])[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[C:7]([C:14](=[O:16])[CH3:15])[C:8]([CH3:12])([CH3:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: C=C(OCC)C1=C(c2ccc(F)cc2)c2ccc(Cl)cc2OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)C1=C(c2ccc(F)cc2)c2ccc(Cl)cc2OC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in (1) described above (140 mg) and 4N hydrochloric acid-dioxane solution (5 mL) were stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo, and to the resultant residue was added a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, filtered through a column of porous diatomite (Chem Elut) and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=98/2 to 90/10) to give the titled compound (121 mg) as a pale yellow powder.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:18]([C:12]1[CH:13]=[N:14][C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[CH:11]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCc2ncc([N+](=O)[O-])cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of 3-nitro-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester (6.14 g, 22 mmol) in CH2Cl2 (60 mL) was added TFA (7 mL). The reaction was stirred for 18 h at RT. After evaporation of the solvent, the residue was taken into water and neutralized with saturated NaHCO3 aqueous solution. The solid was filtered and washed with cold water and dried. The solid was recrystallized from CH3CN to give desired title compound as pale white solid. MS (ES+): 180.1 (M+H)+. Calc'd for C8H9N3O2—179.07.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[CH2:6][O:7][C:8]([O:10][C:11]1[C:18]([CH3:19])=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[CH3:20])=[O:9])([O-:3])=[O:2].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CCO>[N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[CH2:6][O:7][C:8]([O:10][C:11]1[C:12]([CH3:20])=[CH:13][C:14]([CH2:15][OH:16])=[CH:17][C:18]=1[CH3:19])=[O:9])([O-:3])=[O:2]
Reactant: Cc1cc(C=O)cc(C)c1OC(=O)OCc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CO)cc(C)c1OC(=O)OCc1ccccc1[N+](=O)[O-]
Yield: 56.3 %

Procedure:
Added EtOH (0.5 mL) at r.t. to a mixture of 7h (100 mg, 0.3 mmol) and sodium borohydride (12 mg, 0.3 mmol) and then refluxed for 5 minutes. Quenched reaction with 1 m HCl (0.5 mL) and poured into 5% NaHCO3 (15 mL). Aqueous workup (Et2O, MgSO4) followed by concentration in vacuo afforded a yellow oil which was purified by flash chromatography (20 g. 1:1 hexanes/ethyl acetate) to yield 8h (56 mg, 56%) as a crystalline solid: 1H NMR (270 MHz, (CDCl3) d 2.19 (s, 6H), 4.56 (s, 2H), 5.69 (s, 2H), 7.04 (s, 2H), 7.49-7.55 (m, 1H), 7.69-7.72 (m, 2H), 8.15 (d, J=7.9 Hz, 1H); 13C NMR (68 MHz, CDCl3) d 16.1, 64.7, 66.9, 125.4, 127.5, 128.8, 129.3, 130.3, 131.6, 134.1, 138.9, 147.3, 147.69, 152.7.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:7]1=[O:36].[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:11]2[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:7](=[O:36])[N:6]2[CH2:5][C:4]2[CH:37]=[CH:38][CH:39]=[C:2](/[CH:42]=[CH:41]/[C:40]([O:44][CH2:45][CH3:46])=[O:43])[CH:3]=2)=[CH:13][CH:14]=1)#[N:19]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(Br)c2)C1c1ccc(C#N)cc1
Reactant: C=CC(=O)OCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)OCC)C2c2ccc(C#N)cc2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 3-(3-bromobenzyl)-4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 35) (500 mg, 0.84 mmol) in dimethylformamide (7.0 ml) is added bis(triphenylphosphine)palladium(II)chloride (117.3 mg, 0.17 mmol), ethyl acrylate (457.2 μl, 4.18 mmol) and triethylamine (232.9 μl, 1.67 mmol). The reaction is stirred overnight (16 h) at 120° C., then cooled to room temperature, diluted with dimethylformamide (8 ml) and purified directly by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10). The title compound, which is still slightly impure, is isolated (356 mg) and then chromatographed again over silica gel 60 with cyclohexane/ethyl acetate (5:1) as eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][C@@H:22]([C:24]3[CH:35]=[CH:34][C:27]4[O:28][C:29]([CH3:33])([CH3:32])[O:30][CH2:31][C:26]=4[CH:25]=3)[O:21][C:20]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[S:37]1[CH2:41][CH2:40][N:39]2[CH:42]=[C:43]([CH:45]=O)[N:44]=[C:38]12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].P([O-])([O-])([O-])=O>ClCCl>[S:37]1[CH2:41][CH2:40][N:39]2[CH:42]=[C:43]([CH2:45][NH:1][C:2]3[CH:3]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][C@@H:22]([C:24]5[CH:35]=[CH:34][C:27]6[O:28][C:29]([CH3:32])([CH3:33])[O:30][CH2:31][C:26]=6[CH:25]=5)[O:21][C:20]4=[O:36])[CH:5]=[CH:6][CH:7]=3)[N:44]=[C:38]12
Reactant: O=Cc1cn2c(n1)SCC2
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NCc5cn6c(n5)SCC6)c4)C(=O)O3)ccc2O1
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
A solution of (5R)-3-{6-[2-{[(3-aminophenyl)methyl]oxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (200 mg) and 2,3-dihydroimidazo[2,1-b][1,3]thiazole-6-carboxaldehyde (62 mg) (WO94/10178) in dichloromethane (10 ml) was treated under nitrogen with sodium triacetoxy borohydride (340 mg) and stirred at 20° for 1.5 h. The mixture was cooled to 0°, phosphate buffer solution (pH6.5, 20 ml) was added and the mixture was extracted with EtOAc (3×30 ml). The combined organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was purified by SPE. Elution with dichloromethane, dichloromethane-EtOH-ammonia (400:8:1) then (225:8:1) gave the title compound (172 mg). LCMS RT=3.16 min, ES+ve 637 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][C:25]([NH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:26]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)OC)c(NC(=O)Cc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A mixture of dimethyl 2-aminoterephthalate (2.09 g), 2,4-dichlorophenylacetic acid (2.05 g), N,N-dimethylaminopyridine (1.32 g) and dicyclohexylcarbodiimide (2.22 g) in tetrahydrofuran (20 ml) was stirred at room temperature for 2 hr and then at 80° C. for 4 hr. After cooling, the precipitate was filtered off and the filtrate was washed with 1N hydrochloric acid. Chloroform mixture was added to the obtained organic layer, and the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and dried over sodium sulfate. The solvent was distilled away and the residue was washed with water and methanol to give the object compound (2.54 g) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:20]([NH2:22])=[O:21].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:22][C:20](=[O:21])[C@@H:19]([NH:18][C:15]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:17])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[CH:28][CH:29]=1
Reactant: N#Cc1ccc(-c2ccc(C[C@H](N)C(N)=O)cc2)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(N)=O)CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-(tert-Butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid (374 mg), (S)-2-amino-3-(4′-cyanobiphenyl-4-yl)propanamide (Example 3, step (iii), 405 mg) and N-ethyl-N-isopropylpropan-2-amine (0.664 mL) were dissolved in DMF (10 mL) and to the solution was added TBTU (734 mg). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated to dryness, dissolved in dichloromethane (20 mL) and was absorbed onto silica. The product was purified by chromatography on silica eluting with 20% ethyl acetate in isohexane, then 50% ethyl acetate in isohexane and then 100% ethyl acetate to afford after evaporation of the relevant fractions the sub-titled compound (700 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]2)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: OCC1CCNCC1
Product: O=C(NCC(=O)N1CCC(CO)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (200 mg, 0.49 mmol) from example 210 and piperidin-4-ylmethanol (89.0 mg, 0.59 mmol). The title compound was obtained as a solid (25.0 mg, 8% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.02 (1H, m), 8.98 (1H, s), 8.50 (1H, s), 4.47 (1H, m), 4.32 (1H, m), 4.06 (2H, m), 3.83 (1H, m), 3.24 (2H, m), 2.96 (1H, m), 2.51 (1H, m), 1.66 (2H, m), 1.60 (1H, m), 1.11 (1H, m), 1.05 (1H, m), 0.92 (1H, m). MS m/z: 505.31, 507.27 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].[Cl:22][S:23](O)(=[O:25])=[O:24]>>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[CH:17][C:18]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4]
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)Nc1cn2cc(Sc3ccc(S(=O)(=O)Cl)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.5 gms. (0.015 mole) of 2-methoxycarbonylamino 6-(phenylthio) imidazo [1,2-a] pyridine is added portionwise to 45 ml. of chlorosulfonic acid at 0° to -5° C. The reaction mixture is stirred at room temperature for 24 hours. The solution is poured onto ice and the solids are collected by filtration. After repeated washes with water, the crude chlorosulfonic acid derivative is dried at room temperature in vacuo.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20]/[CH:21]=[CH:22]/[CH2:23]Cl>CCC(C)=O>[Cl:20]/[CH:21]=[CH:22]/[CH2:23][N:2]([CH3:1])[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1cccc2ccccc12
Reactant: Cl/C=C/CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(C/C=C/Cl)Cc1cccc2ccccc12
Temperature: 50 °C

Procedure:
30 g (0.175 mol) N-methyl-1-naphthalene methanamine, 100 ml MEK and 29 g (0.210 mol, 1.2 eq.) potassium carbonate are introduced into a reactor, the mixture is heated to 50° C. and 22.4 g (0.202 mol, 1.1 eq.) of (1E)-1,3-dichloro-1-propene added dropwise.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][C:11]([C:9]4[CH:8]=[CH:7][C:6]5[O:1][CH2:2][CH2:3][O:4][C:5]=5[CH:10]=4)=[O:13])[CH2:33][CH2:34]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4ccc5c(c4)OCCO5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow solid (61 mg, 56% yield) following Scheme 3 and in analogy to Example 35 using 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (39 mg, 0.22 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[NH:5][CH:6]1[CH:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[CH:13]=2)[O:8][CH2:7]1)[CH3:2].[ClH:35]>C(Cl)Cl.C(O)(C)C>[ClH:35].[NH2:26][CH2:25][CH2:24][O:23][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]([NH:5][C:4](=[O:34])[O:3][CH2:1][CH3:2])[CH:15]2[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)NC1COc2ccc(OCCNC(=O)OC(C)(C)C)cc2C1Cc1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOC(=O)NC1COc2ccc(OCCN)cc2C1Cc1ccccc1
Temperature: 25 °C

Procedure:
487 mg (1.04 mmol) of [4-benzyl-6-(2-tert-butoxycarbonylamino-ethoxy)-chroman-3-yl]-carbamic acid ethyl ester were dissolved in 10 ml methylene dichloride and 2 ml of a solution of hydrogen chloride in isopropanol (5-6 N) were added and the mixture was stirred over night at room temperature. The reaction mixture was warmed to 40° C., stirred for additional 45 min, and concentrated. The residue was dissolved in water and washed with ether. The aqueous phase was concentrated and the residue co-distilled with toluene to give 463 mg (1.14 mmol, quant.) of the desired product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[ClH:17].[CH2:18]([C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1)[CH3:19]>>[ClH:17].[CH2:18]([C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:3]4[C@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[CH:16][CH:15]=3)=[O:14])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1)[CH3:19]
Reactant: CCc1cc(C)cnc1N1CCNCC1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: CCc1cc(C)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2)CC1
Yield: 66.8 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (332 mg) described in Preparation Example 37 and 1-(3-ethyl-5-methylpyridin-2-yl)piperazine hydrochloride (363 mg) described in Preparation Example 54, the title compound (446 mg) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([NH2:21])=[S:20])=[N:2]1.C(O)C.Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29].N>>[CH2:31]([O:30][C:28]([C:27]1[N:21]=[C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)[S:20][CH:26]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: N
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)n1
Yield: 13.1 %

Procedure:
Compound 161 (0.40 g, 1.4 mmol) was added with ethanol (3.0 mL, 1.5 mmol) and ethyl bromopyruvate (0.10 mL, 0.8 mmol) and after heating under reflux for 18 hours, aqueous ammonia was added to stop the reaction. The precipitated crude product was collected by filtration and purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/2). Then, the product was triturated in ethyl acetate to obtain Compound 169 (41 mg, 17%).