Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](O)=[O:9].C(Cl)(=O)C([Cl:19])=O>CN(C=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([Cl:19])=[O:9]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C=CC(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 3,4-dimethoxycinnamic acid (540 mg), DMF (2 drops) and tetrahydrofuran (10 ml) was added oxalyl chloride (0.27 ml) dropwise. The mixture was stirred at room temperature for 40 minutes, at the end of which time the solvent was distilled off to give 3,4-dimethoxycinnamoyl chloride. The chloride was dissolved in dichloromethane (10 ml) followed by addition of 3-amino-4-(2-methylphenyl)-7,8-dihydrocyclopenta [g] [1]benzopyran-2(6H)-one (582 mg) and N,N-dimethylaniline (0.25 ml). The mixture was then stirred at room temperature for 20 hours, after which it was washed with water, dried (MgSO4) and distilled to remove the solvent. The residue was chromatographed on silica gel and eluted with benzene-acetone (9:1) to give 3-(3,4-dimethoxycinnamoylamino) -4-(2-methylphenyl)-7,8-dihydrocyclopenta[g] 1benzopyran-2(6H)-one as oil. The oil was crystallized from ethanol-isopropyl ether (648 mg, 67.4%). Recrystallization from acetone gave colorless needles, m.p. 159°-160° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([O:13][CH3:14])[CH:7]=1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][N:5]([S:24]([CH3:23])(=[O:26])=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([O:13][CH3:14])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(NCC(OC)OC)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(N(CC(OC)OC)S(C)(=O)=O)ccc1F
Yield: 97.6 %

Procedure:
N-(2,2-dimethoxyethyl)-4-fluoro-3-methoxyaniline (1.46 g, 6.37 mmol) in dichloromethane (20 ml) was treated with pyridine (0.5 g 6.37 mmol) and methanesulphonyl chloride (766 mg, 6.69 mmol) and the mixture stirred until the reaction was complete by tlc. Aqueous work up and removal of solvent in vacuo gave N-(2,2-dimethoxyethyl)-N-methanesulphonyl-4-fluoro-3-methoxyaniline 1.91 g
Reaction SMILES: ClC1[N:7]=[C:6](C)[C:5](CC)=[C:4](C)[N:3]=1.[CH3:12][C:13]1[C:14](I)=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].FC1C(I)=C(C=CC=1)C(O)=O>>[CH3:12][C:13]1[C:14]([N:7]2[CH:6]=[CH:5][CH:4]=[N:3]2)=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: CCc1c(C)nc(Cl)nc1C
Agent: O=C(O)c1cccc(F)c1I
Product: Cc1cccc(C(=O)O)c1-n1cccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 36 substituting 3-methyl-2-iodobenzoic acid for 3-fluoro-2-iodobenzoic acid. 1H NMR (500 MHz, CDCl3): 7.79 (d, J=7.4 Hz, 2H), 7.48 (d, J=7.5 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 6.53 (s, 1H), 2.07 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:17][C:18]1[C:23]([CH2:24][C:25](O)=[O:26])=[CH:22][CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[N:19]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.BrC1C(C2C=CC(Cl)=CC=2)=CC(NNC(=O)CC2C=NC(C(F)(F)F)=CC=2)=NC=1>CC#N>[Br:1][C:2]1[C:3]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:4][C:5]([NH:8][NH:9][C:25](=[O:26])[CH2:24][C:23]2[C:18]([CH3:17])=[N:19][C:20]([C:28]([F:29])([F:31])[F:30])=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Reactant: Cc1nc(C(F)(F)F)ccc1CC(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Cc1ccc(C(F)(F)F)nc1)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)ccc1CC(=O)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Yield: 97 %

Procedure:
The title compound (160 mg, 97%) as a beige powder was prepared from 5-bromo-4-(4-chlorophenyl)-2-hydrazinylpyridine (100 mg, 0.33 mmol), 2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetic acid (75 mg, 0.33 mmol), (i-Pr)2EtN (86 mg, 0.66 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBop, 190 mg, 0.37 mmol) in CH3CN (2.5 mL) by the procedures analogous to those described for N′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetohydrazide (Example 56C). LC/MS (method B): retention time 1.92 min, [M+H]+=499.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Br.Br.[NH:13]1[CH:17]=[C:16]([CH2:18][CH2:19][S:20]C(=N)N)[N:15]=[CH:14]1.[OH-].[Na+]>C(O)C.O>[NH:13]1[CH:17]=[C:16]([CH2:18][CH2:19][S:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[N:15]=[CH:14]1
Reactant: N=C(N)SCCc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(SCCc2c[nH]cn2)nc1

Procedure:
A hot solution of 0.2 g (1.3 mmol) of 2-chloro-5-nitropyridine in 5 ml of ethanol is added to a solution of 0.2 g (1.1 mmol) of S-{2-[1H-imidazol-4-yl]ethyl}isothiourea dihydrobromide in 2 ml of water. The resulting suspension is stirred under nitrogen. The reaction mixture is cooled to 0°-5° C. and a solution of 4 molar equivalents of sodium hydroxide (0.16 g) in 2 ml of water is added dropwise under N2. The reaction mixture is stirred for 1 h at the same temperature and for 3 h at 21° C. The reaction mixture is evaporated to dryness and the residue is subjected to column chromatography (silica gel) eluted with a gradient mixture of chloroform and methanol (1-10%) to provide the title compound which is then crystallized from 2-propanol, M.p.: 147°-148° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N:9]([CH3:25])/[C:10](/[C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12)=[CH:11]\[CH:12]=[N+:13](C)C.COC(O)C.[NH2:31][C:32]1[C:33]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[CH:34][C:35]([O:42][CH3:43])=[C:36]([NH:38]C(N)=N)[CH:37]=1.CN(C)C(N(C)C)=N>COCCO.CCOC(C)=O>[CH3:43][O:42][C:35]1[CH:34]=[C:33]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)[C:32]([NH2:31])=[CH:37][C:36]=1[NH:38][C:25]1[N:9]=[C:10]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)[CH:11]=[CH:12][N:13]=1
Reactant: CN(C)/C(=C\C=[N+](C)C)c1cnn2ccccc12
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1NC(=N)N
Agent: CN(C)C(=N)N(C)C
Agent: COC(C)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: COCCO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
A solution of [(Z)-3-(dimethylamino)-3-pyrazolo[1,5-a]pyridin-3-yl-prop-2-enylidene]-dimethyl-ammonium hexafluorophosphate (Intermediate 70, 116 mg, 0.3 mmol) in 2-s methoxyethanol (2 mL) was added dropwise to a stirred solution of 1-(5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)guanidine (Intermediate 72, 84 mg, 0.30 mmol) and 1,1,3,3-tetramethylguanidine (0.056 mL, 0.45 mmol) in 2-methoxyethanol (2 mL) at r.t. under N2. The resulting solution was sealed into a microwave tube and heated to 120° C. for 0.25 h then cooled to r.t. Further 1,1,3,3-tetramethylguanidine (0.056 mL, 0.45 mmol) was then added and the mixture was stirred at 120° C. for 0.25 h, then at 140° C. for 0.25 h. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (2×5 mL). The aqueous solution was extracted with EtOAc (5 mL) and the organic solution was washed with water (2×3 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1.5-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (69 mg, 53%) as a yellow foam; 1H NMR: 2.25 (3H, d), 2.51 (4H, m), 2.87 (4H, t), 3.73 (3H, s), 4.37 (2H, s), 6.72 (1H, s), 7.07 (1H, m), 7.22 (1H, d), 7.33 (1H, s), 7.40 (1H, m), 7.98 (1H, s), 8.31 (1H, d), 8.52 (1H, d), 8.76 (1H, s), 8.79 (1H, d); m/z: ES+ MH+ 431.
Reaction SMILES: [CH3:1][N:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:6]2=[CH:7][CH:8]=[CH:9][N:5]2[CH2:4][CH2:3]1.FC(F)(F)S([Cl:28])(=O)=O>ClCCl>[Cl:28][C:9]1[N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)[C:6]2=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CN1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Product: CN1CCn2c(Cl)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To tert-butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5 g, 16.37 mmol) in dichloromethane (50.00 mL) at 0° C. was added trifluoromethanesulfonyl chloride (3.64 mL, 34.38 mmol) and the reaction was stirred from 0° C. to room temperature overnight. The reaction was diluted with dichloromethane and washed with water. The layers were separated and the organics were dried over sodium sulfate, filtered and concentrated. Purification of the residue by silica gel chromatography eluting with 10-100% ethylacetate in hexanes afforded tert-butyl 6-chloro-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (4.3 g, 77%), as a yellow solid. ESI-MS m/z calc. 339.2, found 340.3 (M+1)+; Retention time: 1.13 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 6.01 (d, J=3.8 Hz, 1H), 5.91 (d, J=3.7 Hz, 1H), 3.77 (t, J=6.1 Hz, 2H), 3.34 (s, 2H), 3.24 (s, 2H), 2.34 (s, 3H), 2.03 (d, J=13.1 Hz, 2H), 1.74 (t, J=11.1 Hz, 2H), 1.47 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[O:17])[CH:12]=3)[C:7]=2[C:6]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:26]2)=[CH:5][CH:4]=1)#[N:2].[OH-:42].[K+].OO.O>CS(C)=O>[C:1]([C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[O:17])[CH:12]=3)[C:7]=2[C:6]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:26]2)=[CH:5][CH:4]=1)(=[O:42])[NH2:2]
Reactant: [OH-]
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C#N)ccc(N4CCC[C@@H](NC(=O)OCc5ccccc5)C4)c23)CC1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(N4CCC[C@@H](NC(=O)OCc5ccccc5)C4)c23)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.9 %

Procedure:
Step 5 A solution of (R)-benzyl 1-(1-cyano-7-(4-methylpiperazine-1-carbonyl)-9H-carbazol-4-yl)piperidin-3-ylcarbamate (108 mg, 0.196 mmol) in DMSO (2 mL) was treated with 22% aqueous potassium hydroxide (0.208 mL, 0.981 mmol), and then dropwise with a solution of 30% aqueous hydrogen peroxide (0.200 mL, 1.961 mmol). The mixture was stirred at rt for 2.5 h. Water was added, the resulting suspension was stirred at rt for 15 min, and the solid was collected by filtration, washed with water and dried to afford (R)-benzyl 1-(1-carbamoyl-7-(4-methylpiperazine-1-carbonyl)-9H-carbazol-4-yl)piperidin-3-ylcarbamate as an off-white solid (89 mg, 80%). 1H NMR (400 MHz, methanol-d4) δ 8.17 (d, J=8.13 Hz, 1H) 7.81 (d, J=8.35 Hz, 1H) 7.66 (s, 1H) 7.30 (d, J=7.91 Hz, 1H) 7.09-7.26 (m, 5H) 6.82 (d, J=8.35 Hz, 1H) 4.90-5.03 (m, 2H) 3.87-3.99 (m, 1H) 3.57-3.68 (m, 1H) 3.27-3.54 (m, 5H) 3.06-3.19 (m, 4H) 2.69-2.82 (m, 1H) 2.47-2.65 (m, 1H) 1.98-2.11 (m, 1H) 1.83-1.97 (m, 2H) 1.32-1.53 (m, 1H). Mass spectrum m/z 569.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C@@H:11]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]([CH2:20][CH2:21][OH:22])[N:14]=[CH:13][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([O:8][C:9]([NH:10][C@@H:11]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]([CH2:20][CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])[N:14]=[CH:13][C:12]1=2)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@@H]1CCCc2c1cnn2CCO)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCn1ncc2c1CCC[C@H]2NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.2 %

Procedure:
To a solution of [(R)-1-(2-hydroxy-ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-carbamic acid benzyl ester (755 mg, 2.40 mmol) and pyridine (1.45 mL, 18.0 mmol) in dichloromethane was added methanesulfonyl chloride (1.40 mL, 18.0 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 6 hours. The resulting mixture was poured into ice (10 g). The organic layer was then separated and washed with 0.1 N hydrochloric acid and saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (10% methanol in dichloromethane) to afford methanesulfonic acid 2-((R)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydroindazol-1-yl)-ethyl ester (880 mg, 90%) as a white solid. MS calcd. for C18H23N3O5S 393, obsd. (ESI+) [(M+H)+] 394.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]#[N:10])[CH:2]=1.C([O-])([O-])=[O:12].[K+].[K+].CS(C)=O.OO>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([NH2:10])=[O:12])[CH:2]=1
Reactant: N#CCOc1cccnc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)COc1cccnc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
To a mixture of 2-(pyridin-3-yloxy)acetonitrile (100 mg, 0.75 mmol), K2CO3 (103 mg, 0.75 mmol) and DMSO (0.1 mL) in H2O (2 mL) was added H2O2 (0.1 mL, 30%) dropwise in an ice bath and the mixture was stirred at rt for 5 min. It was then concentrated in vacuo and the residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as a white solid (62.2 mg, 55%).
Reaction SMILES: [C:1]1([NH2:10])[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH3:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([NH:10][C:1]1[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH3:9])=[CH:3][CH:2]=1)(=[O:20])[CH3:19]
Reactant: CCOc1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 g of phenetylamine was dissolved in 50 ml of methylene chloride, and 7.0 ml of triethylamine and 3.6 ml of acetyl chloride were added to the solution at 0° C. The solution was stirred at room temperature for 2 hours, washed with water, aqueous solution of citric acid, and saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. After separating the desiccant by filtration, the solution was purified by silica gel column chromatography to obtain 5.52 g of N-acetylphenetylamine, which was white crystal (yield: 82%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][N:10]1[C:15]1[C:24]2[C:19](=[CH:20][C:21]([S:25]([NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][N:30]=3)(=[O:27])=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.CC(C)([O-])C.[Na+].[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44](I)[CH:43]=1>O1CCOCC1>[F:41][C:42]1[CH:43]=[C:44]([N:13]2[CH2:12][CH2:11][N:10]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][N:32]=[CH:31][N:30]=5)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)[CH:9]([CH3:8])[CH2:14]2)[CH:45]=[CH:46][CH:47]=1
Reactant: CC1CNCCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: Fc1cccc(I)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(c2cccc(F)c2)CCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A vial was charged with 1-(2-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide 2,2,2-trifluoroacetate (0.037 g, 0.074 mmol), ruphos palladium(ii) phenethylamine chloride (6.06 mg, 7.42 μmol), and sodium tert-butoxide (0.029 g, 0.297 mmol). Dioxane (0.742 ml) and 1-fluoro-3-iodobenzene (0.013 ml, 0.111 mmol) were added and the reaction was flushed with argon and stirred at 100° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g, gradient elution 0-10% MeOH:DCM) to afford 1-(4-(3-fluorophenyl)-2-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=8.64-8.49 (m, 2H), 8.38-8.21 (m, 3H), 7.97 (d, J=10.1 Hz, 1H), 7.68 (d, J=5.8 Hz, 1H), 7.24 (q, J=8.2 Hz, 1H), 7.05 (br. s., 1H), 6.87-6.76 (m, 2H), 6.56 (dt, J=1.9, 8.2 Hz, 1H), 4.02 (d, J=3.1 Hz, 1H), 3.61-3.44 (m, 3H), 3.29-3.22 (m, 1H), 1.08 (d, J=6.3 Hz, 5H). m/z (ESI) 479.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O.Cl.[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28]([NH2:30])=[NH:29].C(N(CCCC)CCCC)CCC.Cl>>[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28]1[N:30]=[C:11]([OH:13])[C:10]([C:3]2[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[C:16]([OH:18])[N:29]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Reactant: N=C(N)c1cnccn1
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc(-c2cnccn2)nc(O)c1-c1c(F)cc(F)cc1F
Temperature: 25 °C

Procedure:
A mixture of diethyl 2-(2,4,6-trifluorophenyl)malonate (U.S. Pat. No. 6,156,925)(870 mg, 3.0 mmol), 2-pyrazinecarboxamidine hydrochloride (500 mg, 3.15 mmol), and 600 mg of tributylamine is stirred under nitrogen atmosphere at 180° C. for 1 h and cooled to room temperature. The mixture is cooled to room temperature and treated with 1.0 N hydrochloric acid. The precipitates are collected by filtration, washed with water and dried to give 2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)pyrimidine-4,6-diol as a tan solid (401 mg), which is used directly in the next step.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[S-2:15].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH:21]1[CH2:27][N:26]([CH3:28])[C:25](=O)[C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=2[O:22]1>C1(C)C=CC=CC=1>[Cl:18][CH2:19][CH2:20][CH:21]1[CH2:27][N:26]([CH3:28])[C:25](=[S:15])[C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=2[O:22]1
Reactant: [S-2]
Reactant: CN1CC(CCCl)Oc2ccccc2C1=O
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccccc2C1=S

Procedure:
A mixture of 18.5 g (0.0834 mole) of phosphorus pentasulfide and 18.5 g potassium sulfide was ground together and added to a solution of 100 g (0.417 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in dry toluene, the mixture refluxed 24 hr. and filtered. The filtrate was concentrated and partitioned between chloroform and diluted sodium hydroxide. The chloroform layer was concentrated and the residue was crystallized several times from ethanol. Yield of product was 55 g (52%), m.p. 105°-108° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.[Cl:25][C:26]1[CH:27]=[C:28]([N:33]=[C:34]=[O:35])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]3[N:15]=[C:14]([N:16]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:13]=[CH:12][N:11]=3)[CH3:8])[CH2:2]2)=[O:35])[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)Nc2ccc(Cl)c(Cl)c2)C1

Procedure:
The title compound was prepared from 2-[1-(piperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine and 3,4-dichlorophenylisocyanate according to the procedure described in EXAMPLE 29. Mass spectrum (ESI) 510.3 (M+).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:14]([NH:17][NH2:18])(=O)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O>[CH3:15][C:14]1[N:13]=[C:12]([C:11]2[NH:10][CH:9]=[N:8][C:7]=2[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[NH:18][N:17]=1
Reactant: CC(=O)NN
Reactant: CCCCCNc1nc[nH]c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CCCCCNc1nc[nH]c1-c1nc(C)n[nH]1
Temperature: 165 °C
Reaction time: 14 h
Yield: 9.6 %

Procedure:
To the mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (0.40 g, 2 mmol), acetic acid, hydrazide (0.33 g, 4.5 mmol) in 1-butanol (10 mL) was added potassium carbonate (0.10 g, 0.72 mmol). The mixture was sealed and stirred at 165° C. for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative LCMS (method A) to yield the desired product (45 mg, 10% yield). LCMS calculated for C11H19N6(M+H): 235.2; found: 235.1.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([S:22]([CH2:25][C@@H:26]([C@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)[NH:27][OH:28])(=[O:24])=[O:23])[CH2:19]2)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([S:22]([CH2:25][C@H:26]([N:27]([OH:28])[CH:1]=[O:3])[C@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)(=[O:23])=[O:24])[CH2:19]2)=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: O=S(=O)(C[C@H](NO)[C@H]1CCCO1)N1CCc2ccc(Cl)cc2C1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)[C@@H](CS(=O)(=O)N1CCc2ccc(Cl)cc2C1)[C@H]1CCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of formic acid (0.5 ml) and acetic anhydride (0.125 ml) was stirred at 0° C. for 1 hour, then a solution of (1R)-2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-N-hydroxy-1-[(2R)-tetrahydrofuran-2-yl]ethanamine (80 mg, 0.22 mmol) in anhydrous THF (5 ml) was added and the resulting mixture was stirred at RT for 1 hour. The mixture was evaporated under reduced pressure. The residue was taken up with MeOH (5 ml) and heated at 55° C. for 1 hour. The reaction mixture was evaporated under reduced pressure. After purification by crystallization in EtOAc/pentane, the title compound (22) was obtained as a white powder (37 mg, 43%). HPLC, Rt: 3.0 min (purity: 94.1%). LC/MS, M+(ESI): 389.3, M−(ESI): 387.3.
Reaction SMILES: [Br:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[O:14][C:10]=3[CH:9]=2)=[C:4]([N+:22]([O-])=O)[CH:3]=1>CO.C(Cl)Cl.[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[O:14][C:10]=3[CH:9]=2)=[CH:19][C:20]=1[Cl:21]
Reactant: CSc1nc2ccc(CNc3cc(Cl)c(Br)cc3[N+](=O)[O-])cc2o1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CSc1nc2ccc(CNc3cc(Cl)c(Br)cc3N)cc2o1
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a stirred solution of 4-bromo-5-chloro-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline (451 mg, 1.06 mmol) in methanol (80 mL) and DCM (80 mL) was added palladium on activated charcoal (100 mg). The mixture was stirred under hydrogen for 2 h, filtered and concentrated under reduced pressure to give 4-bromo-5-chloro-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine as a light yellow solid (415 mg, 98.6%). 1H NMR (300 MHz, DMSO-d6) δ 7.57-7.60 (m, 2H), 7.35 (d, J=8.1 Hz, 1H), 6.81 (s, 1H), 6.41 (s, 1H), 5.64 (t, 1H), 5.03 (s, 2H), 4.40 (d, J=6.0 Hz, 2H), 2.74 (s, 3H). LCMS (ESI) m/z 399 (M+H)+.