Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH3:14])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7](O)=O)[CH3:2].CC[N:17](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CN(C=O)C.O1CCOCC1.C(Cl)Cl>[CH2:1]([N:3]([CH3:14])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7]#[N:17])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCN(C)c1cc(C(=O)O)cc(C)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCN(C)c1cc(C#N)cc(C)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.7 %

Procedure:
To a solution of 2-(ethyl-methyl-amino)-6-methyl-isonicotinic acid (2.03 g, 8.80 mmol) and DIPEA (3.41 g, 26.4 mmol) in DMF (80 mL) is added PyBOP (5.00 g, 9.61 mmol) at 0° C. The mixture is stirred for 15 min before 0.5 M NH3 in dioxane (52 mL) is added. Stirring is continued at rt for 2 h before the mixture is again cooled to 0° C. Pyridine (4.35 g, 44.8 mmol) followed by trifluoroacetic anhydride (9.29 g, 44.2 mmol) is carefully added and the reaction mixture is stirred for 2 h while warming to rt. The mixture is then stirred at 70° C. for 15 h, cooled to rt, diluted with DCM and washed with 10% aq. citric acid solution followed by sat. aq. Na2CO3-solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-(ethyl-methyl-amino)-6-methyl-isonicotinonitrile (257 mg) as a pale yellow oil; LC-MS: tR=0.58 min, [M+1]+=176.09.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=O)(C)(C)C.[CH3:16][S:17]SC>>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([S:17][CH3:16])[C:9]=1[NH2:8]
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Product: CSc1cccc(F)c1N

Procedure:
This material was prepared for N-t-butoxycarbonyl-2-fluoroaniline and dimethyl disulfide following the general procedure outlined in Example 86. IR and 1H NMR spectra of the product were consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]1([CH:15]=[CH:14][CH:13]=[CH:12][CH:11]1[C:16]([F:19])([F:18])[F:17])[CH2:3][C:4]1[N:8]([CH3:9])[C:7](S)=[N:6][N:5]=1.N1C=CN=C1>>[OH:1][C:2]1([CH:15]=[CH:14][CH:13]=[CH:12][CH:11]1[C:16]([F:19])([F:18])[F:17])[CH2:3][C:4]1[N:8]([CH3:9])[CH:7]=[N:6][N:5]=1
Reactant: Cn1c(S)nnc1CC1(O)C=CC=CC1C(F)(F)F
Agent: c1c[nH]cn1
Product: Cn1cnnc1CC1(O)C=CC=CC1C(F)(F)F

Procedure:
The triazole produced in Example 19 was desulfurized in a manner analogous to that described in Example 18 with respect to an imidazole compound, to produce 3-(1-hydroxy-2'-trifluoromethylbenzyl)-4-methyl-1,2,4-triazole.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:19])[CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.CCOCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:19])[CH:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH3:12])=[CH:7][CH:8]=1
Reactant: CCC(C(=O)c1ccc(OC)cc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(C(=O)c1ccc(O)cc1)c1ccccc1
Temperature: 220 °C

Procedure:
25.4 G. (0.10 mole) 1-(4'-methoxyphenyl)-2-phenyl-n-butan-1-one and 34.5 g. (0.30 mole) pyridine hydrochloride are melted and refluxed at 220° C. for one hour while being agitated. The melt while still liquid is poured into ice water and the precipitate dissolved in 400 ml. ether. After washing the etheric solution with water, it is shaken out with 1 N sodium hydroxide solution. The aqueous alkaline solution is acidified with 5 N hydrochlc.ric acid and extracted with 500 ml. ether. The organic phase is washed with water and dried over sodium sulfate. The solvent is removed in vacuo and the crude product is crystallized from dilute ethanol. Obtained are colorless crystals having a melting point of 131° C.; Rf 0.45 [toluene/ethyl acetate (9/1)]; yield: 16.3 g. (68%).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]#[N:17])[C:10]([OH:12])=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]#[N:17])[C:10]([OH:12])=[O:11])[N:8]=1
Reactant: N#CCON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: N#CCON=C(C(=O)O)c1csc(N)n1
Yield: 92.9 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetic acid (syn isomer, 2.54 g) and conc. hydrochloric acid (3 ml) in methanol (30 ml) was stirred at room temperature for an hour. After removing methanol from the resultant mixture in vacuo, water was added to the residue and adjusted to pH 3.3 with an aqueous solution of sodium bicarbonate under ice-cooling. The precipitates were collected by filtration to give 2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetic acid (syn isomer, 2.1 g)
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:18][CH2:19][C@@H:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=1)[OH:21]>>[OH:21][C@H:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=1)[CH2:19][NH:18][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)Cc1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from [4-(4-oxo-piperidine-1-yl)-phenyl]-acetic acid (which was obtained in Example 149) and N-[5-(2-amino-(1 R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a pale yellowish solid; mp >140° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.25-1.40 (m, 2H), 1.75-1.95 (m, 2H), 2.50-3.60 (m, 7H), 2.88 (s, 3H), 3.16 (s, 2H), 4.47 (dd, J=8.0, 4.1 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 6.84 (d, J=8.3 Hz, 2H), 6.95 (dd, J=8.2, 1.7 Hz, 1H), 7.05 (d, J=8.3 Hz, 2H), 7.16 (d, J=1.7 Hz, 1H); MS (ES) m/z: 464.1 (MH+); HRMS Calcd. for C22H28N3O6S(M−H)−: 462.1704. Found: 462.1696.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[CH:35]=[C:36]([C:39]([F:40])([F:41])[F:42])[CH:37]=[CH:38][C:32]=3[F:31])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C(F)(F)F)ccc3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 12.6 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 2-fluoro-5-(trifluoromethyl)aniline (0.071 g, 0.396 mmol), THF (10.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.018 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.14-3.17 (s, 2H), 7.33-7.41 (m, 3H), 7.53-7.62 (m, 3H), 8.92 (d, J=6.6 Hz, 1H), 9.40 (s, 1H), 10.32 (s, 1H), 11.25 (s, 1H); MS [M+H]+: 537.33.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl:61][CH2:62][C:63](=[O:80])[C@@H:64]([NH:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.[OH-].[Na+]>>[Cl:61][CH2:62][C@H:63]([OH:80])[C@@H:64]([NH:72][C:73]([O:75][C:76]([CH3:78])([CH3:77])[CH3:79])=[O:74])[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CCl
Temperature: 30 °C
Yield: 99 %

Procedure:
Glucose dehydrogenase (manufactured by Amano Enzyme) 1250 U, glucose 3 g, NADP 4 mg, (3S)-1-chloro-3-tert-butoxycarbonylamino-4-phenyl-2-butanone 0.25 g were added to 22.5 ml of a cell-free extract of E. coli HB101 (pNTOM4) prepared in Example 7, and the mixture was stirred at 30° C. while adjusting to pH 6.5 by dropwise addition of 5 M sodium hydroxide. (3S)-1-chloro-3-tert-butoxycarbonylamino-4-phenyl-2-butanone (0.25 g) was added at 2 hr, 4 hr and 6 hr from the start of the reaction and 1.25 g thereof was added at 8 hr from the start of the reaction, and the mixture was reacted for 31 hr. After completion of the reaction, the reaction mixture was extracted with toluene, desolvated and the extract was analyzed in the same manner as in Example 8. As a result, (2R,3S)-1-chloro-3-tert-butoxycarbonylamino-4-phenyl-2-butanol (yield 99.0%, diastereomeric excess 99.8% d.e.) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16]([NH:18]C(C)(C)C)=O)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16]#[N:18])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(F)c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ncccc1CCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.5 %

Procedure:
A solution of 3-[2-(3-fluorophenyl)ethyl]-N(1,1-dimethylethyl)-2-pyridine carboxamide (36.4 g, 0.121 mole) in 123 mL (202.3 g, 1.32 mole) of phosphorous oxychloride is heated at 110° C. for 3.5 hours and stirred at ambient temperature an additional 15 hours. The reaction is quenched with ice and water and the pH of the solution is brought to 8 by the addition of a saturated aqueous solution of potassium carbonate. The product is extracted into ethyl acetate and the solution is concentrated to a residue. Following purification by silica gel chromatography and trituration with pentane, 16.2 g (0.072 mole) of product is obtained in 60% yield.
Reaction SMILES: O=[C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[N:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)=[N+:15]=[N-:16].[O-]CC.[Na+].O>C(O)C>[CH2:24]([NH:23][C:21]([C:20]1[CH:26]=[CH:27][C:17]([N:14]2[C:2]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[C:3]([C:4]([OH:6])=[O:5])[N:16]=[N:15]2)=[CH:18][CH:19]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CC(=O)c1cccs1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2-c2cccs2)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 89.3 %

Procedure:
Ethyl 3-oxo-3-(2-thienyl)propanoate (500 mg, 2.50 mmol) and 4-azido-N-ethylbenzamide (500 mg, 2.50 mmol, 1.0 eq.) obtained in Example 43a) were dissolved in ethanol (20 ml), a solution of sodium ethoxide in ethanol (20%, 1.3 g, 3.82 mmol, 1.5 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 7 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1). The organic layer was extracted with 2% aqueous sodium carbonate solution. The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (764 mg, 89%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[ClH:22].[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(Cl)c(OC2CCNCC2)c1

Procedure:
To a stirred solution of 2-chloro-5-fluorophenol (6 g, 0.0413 mole) in DMF (20 mL) was added cesium carbonate (26.89 g, 0.00827 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (11.54 g, 0.04137 mole). The reaction mixture was heated at 80° C. for overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 230-400 mesh (2% ethyl acetate in hexane) to afford 8.9 g (65%) of 4-(2-chloro-5-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 330.12 (M+1)+, 100%. A solution of 4-(2-chloro-5-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (8.9 g, 0.027 mole) in ethyl acetate.HCl (10 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with ether to afford 6.54 g (92%) of. LCMS: 230.07 (M+1)+, 100%, 1H NMR (DMSO-d6): δ 9.6-9.1 (bs, 2H), 7.55-7.45 (t, 1H), 7.35-7.2 (d, 1H), 6.9-6.8 (t, 1H), 4.9-4.7 (s, 1H), 3.26-3.0 (s, 4H), 2.2-2.06 (s, 2H), 2.0-1.8 (s, 2H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[C:12]1([CH2:18][C:19]([O:21][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][O:22]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)OC1CCCCO1

Procedure:
To a saturated solution of anhydrous p-toluenesulphonic acid in dry dichloromethane (25 ml) successively phenylacetic acid (4a) (0.581 g, 4.26 mmol) and 3,4-dihydro-2H-pyran (3 ml, 32.9 mmol) were added, and the resultant solution was stirred at room temperature until the starting material 4a disappeared (ca. 1 hour). To the reaction mixture triethylamine (1 ml, 7.2 mmol) was added and the volatiles were evaporated. The obtained crude tetrahydro-2H-pyran-2-yl 2-phenylacetate (5a) was immediately utilized in the next step of the synthesis.
Reaction SMILES: ClC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.N1C2C(=CC=CC=2)C=C1.BrCCCCC[Cl:32]>>[Cl:32][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: ClCCCCCCn1ccc2ccccc21
Reactant: ClCCCCCBr
Agent: c1ccc2[nH]ccc2c1
Product: ClCCCCCn1ccc2ccccc21
Yield: 80 %

Procedure:
According to the procedure used for the synthesis of 1-(6-chlorohexyl)-1H-indole, 1-H-indole (0.585 g, 5.00 mmol) and 1-bromo-5-chloropentane (0.928 g, 5.00 mmol) gave the desired product (0.890 g, 80%). 1H NMR (CDCl3) δ 7.76-7.51 (m, 1H), 7.44-6.96 (m, 4H), 6.60-6.38 (m, 1H), 4.11 (t, 2H, J=6.8 Hz), 3.47 (t, 2H, J=6.4 Hz), 1.97-1.79 (m, 2H), 1.79-1.61 (m, 2H), 1.58-1.32 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.Cl.C[N:27](C)CCCN=C=NCC.[NH4+].[Cl-].C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([NH2:27])=[O:20])[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1csc(Nc2ncc(Br)cc2Sc2cccc(C(=O)O)c2)n1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1csc(Nc2ncc(Br)cc2Sc2cccc(C(N)=O)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)benzoic acid (0.35 g, 0.83 mmol) was dissolved in DMF (5 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.24 g, 1.2 mmol), NH4Cl (0.133 g, 2.5 mmol) and HOBT-H2O (0.19 g, 1.2 mmol) were added. Triethylamine (0.29 mL, 2.1 mmol) was added last. The reaction stirred at room temperature overnight. The material was diluted with water and the solid was filtered to give the title compound (0.23 g, 67% yield). 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 6.40 (bs, 1H), 7.48 (s, 1H), 7.53-7.56 (m, 2H), 7.90-7.96 (m, 2H), 8.08 (s, 1H), 8.27 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])=[N:6][C:7]=1[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.BrC1N=C(N[C@@H](C2C=CC=CC=2)C)C(N)=NC=1C.N1C2C=CC=C(B(O)O)C=2C=CC=1.[C:59](=O)([O-])[O-:60].[K+].[K+]>O.CN(C)C=O.[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>[CH3:1][C:2]1[N:3]=[C:4]2[NH:27][C:59](=[O:60])[N:18]([C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:5]2=[N:6][C:7]=1[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: Cc1nc(N)c(N[C@H](C)c2ccccc2)nc1-c1cccc2ncccc12
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: Cc1nc(N)c(N[C@H](C)c2ccccc2)nc1Br
Agent: OB(O)c1cccc2ncccc12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2[nH]c(=O)n([C@H](C)c3ccccc3)c2nc1-c1cccc2ncccc12
Yield: 67 %

Procedure:
5-Methyl-N2—((R)-1-phenylethyl)-6-(quinolin-5-yl)pyrazine-2,3-diamine. (R)-6-Bromo-5-methyl-N2-(1-phenylethyl)pyrazine-2,3-diamine (0.534 g, 1.74 mmol), quinoline-5-boronic acid (0.331 g, 1.91 mmol), tetrakis(triphenylphosphine) palladium (0.20 g, 0.175 mmol), and potassium carbonate (0.96 g, 6.96 mmol) in water (4 mL) and dimethylformamide (15 mL) was reacted according to General Procedure B and purified via Biotage silica gel chromatography (0-10% methanol in dichloromethane, 40M column) and the resultant solid triturated with water/methanol to afford the title compound (0.42 g, 67% yield). MS (ESI) m/z 356.4 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]([CH3:24])([CH3:23])[C:12]([N:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[N:25]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([N:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:12](=[O:13])[C:11]([CH3:24])([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:3]=1)[CH3:23])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: NCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)c1
Temperature: 100 °C

Procedure:
A mixture of 2-(3-chloro-4-nitrophenyl)-N,N-diisobutyl-2-methylpropanamide (2.39 g), 3-piperidino-propylamine (1.9 g, 2 eq) and potassium carbonate (1.8 g, 2 eq) in DMF (40 ml) is heated at 100° C. for 24 hours then cooled down to ambient temperature. Water and ethyl acetate are added to the medium. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure. Purification of the residue obtained by flash chromatography on silica gel (eluent: dichloromethane 100% to dichloromethane/methanol 6:4) produces the expected compound in the form of a yellow oil (1.6 g, 51% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:22][CH2:23][CH2:24][C:25](N(OC)C)=[O:26])[CH:11]=[C:12]3[C:17]=2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]3[CH3:21])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:32]1[S:33][CH:34]=[C:35]([Cl:37])[N:36]=1>C1COCC1>[Cl:37][C:35]1[N:36]=[C:32]([C:25](=[O:26])[CH2:24][CH2:23][CH2:22][N:10]2[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])=[C:17]3[C:12]([N:13]([CH3:21])[C:14](=[O:20])[N:15]([CH3:19])[C:16]3=[O:18])=[CH:11]2)[S:33][CH:34]=1
Reactant: Clc1csc(Br)n1
Reactant: CON(C)C(=O)CCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCC(=O)c3nc(Cl)cs3)cc2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isopropylmagnesium chloride lithium chloride complex solution (1.3 M in THF, 2.067 ml, 2.69 mmol) was added dropwise to a solution of 4-(5-(3-cyanophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-N-methoxy-N-methylbutanamide (1 g, 2.442 mmol) and 2-bromo-4-chlorothiazole (Intermediate Q, step 2) (0.533 g, 2.69 mmol) in THF (24.42 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes. A further portion of isopropylmagnesium chloride lithium chloride complex solution (1.3 M in THF, 2.067 ml, 2.69 mmol) was added at 0° C. and the mixture was stirred for a further 30 minutes at 0° C. The reaction was quenched with saturated NH4Cl(aq) (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were washed with saturated NaHCO3(aq) (10 mL), dried over magnesium sulfate and evaporated under reduced pressure. Trituration with methanol afforded the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:9]([O:11]N1C(=O)CCC1=O)=O)[CH:2]=[CH2:3].Cl.[CH3:27][NH:28][O:29][CH3:30].C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:8]([C:9](=[O:11])[N:28]([O:29][CH3:30])[CH3:27])[CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc(C(=O)ON2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1cc(C(=O)N(C)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (7(b)) (2.00 g), N,O-dimethylhydroxylamine hydrochloride (0.62 g), triethylamine (0.86 ml) and dichloromethane (60 ml) was stirred at 50 for 30 min and then allowed to warm to ambient temperature and stirred for a further 16 h. The mixture was poured onto a flash column and eluted with ethyl acetate/hexane (40:60) to give 3-(N-methyl-methoxycarbamoyl)-5-nitro benzoic acid allyl ester (7(c)) as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]([O:35][CH3:36])=[CH:8][C:9]2[CH2:10][CH2:11][N:12]3[C:18]4[C:19](=[O:29])[N:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=4[C:16]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[C:13]3[C:14]=2[CH:15]=1)=[O:4].[CH2:37]([N:39](CC)[CH2:40]C)C.CNC>CN(C=O)C.C1COCC1>[CH3:37][N:39]([CH3:40])[CH2:2][C:3]([NH:5][C:6]1[C:7]([O:35][CH3:36])=[CH:8][C:9]2[CH2:10][CH2:11][N:12]3[C:18]4[C:19](=[O:29])[N:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=4[C:16]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[C:13]3[C:14]=2[CH:15]=1)=[O:4]
Reactant: CCN(CC)CC
Reactant: COc1cc2c(cc1NC(=O)CCl)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: CNC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1NC(=O)CN(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 60 °C

Procedure:
A suspension of 392 mg of 22a in 3 ml of DMF was treated with 0.5 ml of triethylamine and 2 ml of a 2M solution of dimethylamine in THF. The reaction mixture was sealed and heated at an oil bath at 60° C. for 40 min. The clear solution was poured onto water and extracted with ethyl acetate. The extract was washed, dried and concentrated and the residue was purified by chromatography over silicagel, using a gradient of CH2Cl2-methanol. The material thus isolated was triturated with diethylether, to provide 438 mg of crystalline material.