Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25]>>[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CN1CCC(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(C4CCN(C)CC4)cc3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 41 %

Procedure:
Following Example 247c, 282c and 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d were reacted to give 282d in 41% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C:6]2([NH:35][C:36](=O)[O:37]C1C=CC=CC=1)[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2].[NH:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]2)[CH2:47][CH2:46]1.C(Cl)Cl.CO.C(O)(C(F)(F)F)=O>O1CCCC1.C(#N)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:13])=[O:14])[C:7](=[O:25])[C:6]2([NH:35][C:36]([N:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH2:52][CH2:53][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:55][CH2:56]2)[CH2:47][CH2:46]1)=[O:37])[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Reactant: CCOc1ncccc1C1(NC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Solvent: CO
Solvent: O
Solvent: CC#N
Product: CCOc1ncccc1C1(NC(=O)N2CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
100 mg (0.16 mmol) of phenyl [5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate (prepared according to Example 1, process steps 1a) to 1f)) were initially charged in 8 ml of anhydrous tetrahydrofuran (dried over molecular sieve), and 65.8 mg (0.24 mmol) of tert-butyl 4-piperidin-4-ylpiperazine-1-carboxylate were added. The mixture was then stirred at room temperature overnight. The progress of the reaction was monitored by TLC (silica gel, CH2Cl2/MeOH 9:1) and LCMS (RP, mobile phases acetonitrile/water and 0.01% TFA). The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane and extracted with 2 N aqueous sodium hydroxide solution (1×). The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude mixture was purified by column chromatography (5 g NP-SiO2 cartridge, Chromabond) using dichloromethane/methanol in a ratio of 98:2 as mobile phase. This gave 55.3 mg (0.07 mmol, 43%) of the desired product, which was directly used in the next reaction step for Boc deprotection.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[N+:17]([O-])=O.CN(C=O)C.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCCCCC>[NH2:17][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:8]=1[Cl:7])[C:12]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:14]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Nc1cc(C(=O)Nc2ccccc2)ccc1Cl
Yield: 68.9 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (2.5 mL, 28.66 mmol), 4-chloro-3-nitrobenzoic acid (4.02 g, 19.94 mmol), DMF (1.0 mL, 12.92 mmol), and aniline (3.6 mL, 39.51 mmol) to afford the product (3.39 g) after trituration in hexane; m.p. 194-197° C. after recrystallization from ethyl acetate.
Reaction SMILES: N([CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)=[N+]=[N-].FC1C(C2N=NC(C)=CC=2)=NC=CC=1.[Cl:32]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>ClCCCl>[Cl:32][CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: [N-]=[N+]=NCc1ccc(-c2ncccc2F)nn1
Agent: Cc1ccc(-c2ncccc2F)nn1
Solvent: ClCCCl
Product: Fc1cccnc1-c1ccc(CCl)nn1
Temperature: 90 °C

Procedure:
3-(azidomethyl)-6-(3-fluoropyridin-2-yl)pyridazine. A solution of 3-(3-fluoropyridin-2-yl)-6-methylpyridazine (200 mg, 1.05 mmol) in 5 mL of DCE was treated with trichloroisocyanuric acid (98 mg, 0.42 mmol). The mixture was heated at 90° C. for 1 h. The mixture was cooled to RT and the precipitate was filtered off with a fritted funnel and rinsed with 2×20 mL of DCM. The brown solid was discarded. The filtrate was washed with 2×5 mL of 0.5 M NaOH (aq.) followed by brine (5 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (55-75% EtOAc in hexanes) to give 3-(chloromethyl)-6-(3-fluoropyridin-2-yl)pyridazine as a brown crystalline solid. MS (ESI, pos. ion) m/z: 224.0 (M+1). A solution of the 3-(chloromethyl)-6-(3-fluoropyridin-2-yl)pyridazine in 1 mL of DMF at RT was treated with NaN3 (69 mg, 1.05 mmol) and stirred at RT for 5 h. The mixture was filtered through a fritted funnel and the collected solid was rinsed with 2×5 mL of EtOAc. The solid was discarded and the filtrate was concentrated and the crude material was purified by silica gel chromatography (35-75% EtOAc in hexanes) to give 3-(azidomethyl)-6-(3-fluoropyridin-2-yl)pyridazine (100 mg, 41% yield) as an off white amorphous solid. MS (ESI, pos. ion) m/z: 231.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (1 H, m), 8.27 (1 H, d, J=8.8 Hz), 8.00 (1 H, m), 7.94 (1 H, m), 7.69 (1 H, dt, J=8.4, 4.2 Hz), 4.89 (2 H, s). 19F NMR (376 MHz, DMSO-d6) δ ppm-121.47.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C:20]1([CH3:33])[CH3:32])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:17][N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][C:20]2([CH3:33])[CH3:32])[C:13]1=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)C(C)(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a solution of (25)-2-(benzyloxycarbonylamino)-4-(1-(tert-butoxycarbonyl)-3,3-dimethylpiperidin-4-ylamino)butanoic acid (3.59 g, 7.74 mmol) in DMF (20 mL) was added DIEA (4.1 mL, 23 mmol) and HBTU (3.5 g, 9.3 mmol). The mixture stirred at ambient temperature overnight. The mixture was poured into 1 N NaOH solution and extracted into ethyl acetate. The organic layer was washed with 1 N HCl solution and brine, dried over MgSO4, filtered and concentrated under vacuum. Flash chromatography (7:3 EtOAc:hexanes) gave tert-butyl 4-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (0.81 g, 1.8 mmol, 23%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(O)(C(F)(F)F)=O>O1CCCC1.O.CO>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Br)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of commercially available (6-bromopyridin-2-yl)methanol (20.0 g, 0.106 mol), phthalimide (20.4 g, 0.138 mol), and triphenylphosphine (36.2 g, 0.138 mol), and 1,1′-(azodicarbonyl)-dipiperidine (34.8 g, 0.138 mol) in anhydrous tetrahydrofuran (1 L) was stirred at room temperature overnight. The precipitate was collected by vacuum filtration and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the solid residue was triturated with methanol with sonication. A214.1 was collected by vacuum filtration and was dried well to give 24.1 g as a white solid. The filtrate still contained significant product which could be isolated as a second crop with methanol trituration. The compound had an HPLC retention time=2.32 min. (Column: Chromolith SpeedROD 4.6×50 mm−4 min.; Solvent A=10% MeOH, 90% H2O, and 0.1% TFA; Solvent B=90% MeOH, 10% H2O, and 0.1% TFA) and a LC/MS M+1=317.15 and 319.15.
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:16])(=[O:15])[CH2:14][C:8]=2[CH:7]=[C:6]([NH:25][CH:26]=[O:27])[CH:5]=1>O.CO>[Na+:2].[Cl:3][C:4]1[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([O-:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:15])(=[O:16])[CH2:14][C:8]=2[CH:7]=[C:6]([NH:25][CH:26]=[O:27])[CH:5]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)[O-])cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium hydroxide (0.0108 g, 0.27 mmol) in water (0.1 mL) was added to the solution of Example 7 (0.104 g, 0.27 mmol) in methanol (5 mL) and stirred at 25° C. for 15 min, the solvent was removed and dried to obtain the title compound. Yield: 0.11 g, (100%); 1H NMR (DMSO-d6, 300 MHz): δ 2.58 (s, 3H, CH3), 5.16 (s, 2H, CH2), 7.69 (d, 1H, Ar), 7.87 (d, 1H, Ar), 7.95 (s, 1H, Ar), 8.11 (s, 1H, Ar), 8.30 (s, 1H, CHO), 10.78 (s, 1H, NH); MS: m/e (ES−) 380 (M−Na); analysis: C16H11ClNNaO6S.2H2O requires C, 43.70; H, 3.44; N, 3.81; Cl, 8.06; S, 7.29. found: C, 42.88; H, 3.19; N, 3.04; Cl, 8.69; S, 7.67%.
Reaction SMILES: [N:1]1([C:7](=[O:15])[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[CH3:16][C:17]1[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:21]=[CH:20][C:18]=1[N:19]=[C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:15]
Reactant: Cc1c(N)cccc1C(F)(F)F
Reactant: O=C(C(=O)N1CCNCC1)c1cccs1
Product: Cc1c(N=C(C(=O)N2CCNCC2)c2cccs2)cccc1C(F)(F)F

Procedure:
Intermediate 13 was generated from 1-piperazin-1-yl-2-thiophen-2-yl-ethane-1,2-dione and 2-methyl-3-(trifluoromethyl)aniline using general method L.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=1[CH3:22].B(Br)(Br)Br.C1CCCCC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[CH3:22]
Reactant: CCCn1nc(-c2ccc(OC)cc2C)c2cccc(F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCn1nc(-c2ccc(O)cc2C)c2cccc(F)c21
Yield: 98.5 %

Procedure:
Prepared according to Method D step C from 7-fluoro-3-(4-methoxy-2-methylphenyl)-1-propyl-1H-indazole (0.268 g, 0.90 mmol), boron tribromide (0.275 mL, 2.90 mmol) and 1.0 mL of cyclohexene to give the product (0.252 g) as a white solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C(O[C:44]([C@H:46]1[C@@H:51]([NH:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([F:60])=[C:56]([Cl:61])[CH:55]=2)[C@H:50]2[CH2:62][C@@H:47]1[CH2:48][CH2:49]2)=[O:45])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[Cl:61][C:56]1[CH:55]=[C:54]([CH:59]=[CH:58][C:57]=1[F:60])[CH2:53][N:52]1[C:17](=[O:18])[C:16]([C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=3[S:13](=[O:15])(=[O:14])[N:12]=2)=[C:44]([OH:45])[C@H:46]2[C@@H:51]1[C@H:50]1[CH2:62][C@@H:47]2[CH2:48][CH2:49]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)c(Cl)c3)C1=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.258 g, 0.774 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.156 g, 0.814 mmol) and N-methylmorpholine (0.170 mL, 1.55 mmol) were added sequentially to a solution of (1S,2R,3S,4R)-3-(3-chloro-4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.252 g, 0.773 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (20 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (1.00 mL, 3.09 mmol) was added and the reaction mixture was heated at 60° C. for 1 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 40 to 100% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)—N-{3-[3-(3-chloro-4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.196 g, 0.332 mmol, 43%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.04-1.21 (4H, m), 1.40-1.60 (3H, m), 2.54-2.63 (1H, m), 3.05 (3H, s), 3.31-3.40 (2H, m), 3.55-3.58 (1H, m), 4.45 (1H, d, J=16.1 Hz), 4.91 (1H, d, J=14.7 Hz), 7.31-7.35 (2H, m), 7.51-7.57 (4H, m), 10.17 (1H, s), 13.96 (1H, s). LC-MS (ESI) calcd for C25H24ClFN4O6S2 594.08, found 595.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:28]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:33]([CH:30]5[CH2:31][CH2:32][O:28][CH2:29]5)=[O:34])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C1CCOC1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: O=C(C1CCOC1)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 52 %

Procedure:
According to the procedure for compound 398 using tetrahydrofuran-3-carboxylic acid (35 mg, 0.30 mmol) afforded 22.2 mg (52% yield) of 478, as a solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.CCN(CC)CC.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>C(Cl)Cl>[C:28]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](N)C2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](NC(=O)c3cccnc3)C2)cc1
Yield: 78.8 %

Procedure:
A solution of 397 (100 mg, 0.38 mmol), Et3N (160 μL, 1.14 mmol) and nicotinoyl chloride HCl salt (68 mg, 0.38 mmol) in DCM (2 mL) was stirred at room temperature for 1 hour and quenched by adding saturated NH4Cl sat solution (5 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated to produce a residue which was purified by flash chromatography using 5% MeOH in DCM as an eluent to afford the title compound (110 mg, 79% yield). LRMS: (calc) 367.2; (found). 368.1 (M+H1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.[H-].[Na+].[CH3:11]I>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:11])[C:4](=[O:8])[CH:3]=1
Reactant: CI
Reactant: Oc1cc(Br)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc(Br)cc1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
To a solution of 4-bromo-2-hydroxypyridine (0.10 g, 0.57 mmol) in THF (5.0 mL) was added, portion wise, NaH (60% dispersion in mineral oil, 0.02 g, 0.86 mmol). The resulting solution was stirred at room temperature for 5 min followed by addition of methyl iodide (0.11 mL, 1.72 mmol). The reaction mixture was then allowed to stir overnight at room temperature. After the completion of reaction, THF was distilled off, added water and extracted with ethyl acetate (3×25 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.10 g, 92%). 1H NMR (DMSO-d6, 400 MHz): δ 3.43 (s, 3H), 6.45 (dd, J=2.40 and 7.20 Hz, 1H), 6.69 (d, J=2.40 Hz, 1H) and 7.68 (d, J=7.20 Hz, 1H). MS: 188.05 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:15](=[O:17])[CH2:14][CH2:13][CH2:12][C:11]=3[O:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][NH2:20]>>[CH3:19][N:20]1[C:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[C:16]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]1=[O:10]
Reactant: CN
Reactant: O=C1CCCc2oc(=O)cc(-c3ccccc3)c21
Product: Cn1c2c(c(-c3ccccc3)cc1=O)C(=O)CCC2

Procedure:
Prepared from 4-phenyl-5,6,7,8-tetrahydro-cumarin- 5-one and methanolic methylamine at ambient temperature.
Reaction SMILES: C([O:8][P:9]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:22]([O:32][P:33]([O:43]CC2C=CC=CC=2)([O:35]CC2C=CC=CC=2)=[O:34])[CH:21]=1)([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>[C].[Pd].C(O)C>[P:9]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:22]([O:32][P:33]([OH:35])([OH:43])=[O:34])[CH:21]=1)([OH:11])([OH:10])=[O:8]
Reactant: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1ccc(C2CCCCC2)c(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: O=P(O)(O)Oc1ccc(C2CCCCC2)c(OP(=O)(O)O)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.1 %

Procedure:
To an ethanol solution (10 ml) of 1,3-bis(dibenzylphosphonooxy)-4-cyclohexylbenzene (1.75 g), 5% palladium-carbon (50% water-containing product) (256 mg) was added and stirred under a hydrogen atmosphere at room temperature for 14 hours. After the removal of the catalyst by filtration, the filtrate was concentrated, to give the light yellow title compound (805 mg, yield: 93%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[N:10]=[N:9][NH:8][C:7]=2[C:6]([N+:12]([O-])=O)=[CH:5][CH:4]=1)#[N:2]>CO.[Pd]>[C:1]([C:3]1[C:11]2[N:10]=[N:9][NH:8][C:7]=2[C:6]([NH2:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc([N+](=O)[O-])c2[nH]nnc12
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(N)c2[nH]nnc12
Yield: 94.8 %

Procedure:
To a solution of 4-cyano-7-nitrobenzotriazole (120 mg, 0.63 mmol) in methanol (250 ml) was added 10% Pd/C (1.0 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure for 4 hrs. The reaction mixture was flushed with argon and 10% Pd/C (1.0 g) was additionally added and a hydrogen atmosphere was maintained at balloon pressure for 1 hr. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/CH2Cl2) gave the desired product (95 mg, 94%). 1H NMR (CD3OD): δ7.58 (d, 1H), 6.53 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH:15]3[CH3:20])[N:11]=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][C@H:22]3[CH3:27])[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[C:37]([NH2:38])=[N:36][C:35](Cl)=[C:34]([Cl:40])[N:33]=1)=[O:31]>C(O)(C)C>[CH3:28][O:29][C:30]([C:32]1[N:33]=[C:34]([Cl:40])[C:35]([N:17]2[CH2:18][CH2:19][N:14]([C:12]3[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[C:10]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C@H:22]4[CH3:27])[N:11]=3)[CH:15]([CH3:20])[CH2:16]2)=[N:36][C:37]=1[NH2:38])=[O:31]
Reactant: CC1CNCCN1c1cc(-c2ccc(F)cc2)nc(N2CCOC[C@H]2C)n1
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1N
Solvent: CC(C)O
Product: COC(=O)c1nc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCOC[C@H]4C)n3)C(C)C2)nc1N

Procedure:
Heat a mixture of 4-[4-(4-fluoro-phenyl)-6-(2-methyl-piperazin-1-yl)-pyrimidin-2-yl]-3-(R)-methyl-morpholine with 1.1 equivalents of 3-amino-5,6-dichloro-pyrazine-2-carboxylic acid methyl ester (Cragoe et. al. J. Med. Chem., 1967, 10, 66-75) in isopropanol at 85° C. for 12 h. Concentrate the mixture under reduced pressure, and then partition between 10% NaOH and EtOAc. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH:8]1([SH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:15][C:16]1[N:24]=[C:23](Cl)[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[Cl-].[Na+].O>[NH2:15][C:16]1[N:24]=[C:23]([S:14][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: SC1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(SC2CCCCC2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (256 mg, 6.4 mmol, 60% in mineral oil) were added cyclohexanethiol (2 ml, 16 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was heated at 100° C. for 3.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (112 mg, yield 86%).