Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:53]3[CH2:54][CH2:55][CH:50]([CH3:49])[CH2:51][CH2:52]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-methyl piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethyl-formamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH2:24]([N:26]1[C:30]([C:31](O)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1)[CH3:25]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:31]([C:30]2[N:26]([CH2:24][CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=2)=[O:32])=[O:10])[N:12]=1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: CCn1nc(C)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=464.4.
Reaction SMILES: [C:1]1(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[O:9])O1.FC(F)(F)C(O)=O.[NH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26]>C(O)(=O)C>[O:26]=[C:20]1[CH:19]([N:18]2[C:3](=[O:9])[C:4]3=[CH:8][S:7][CH:6]=[C:5]3[C:1]2=[O:10])[CH2:24][CH2:23][C:22](=[O:25])[NH:21]1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2cscc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3cscc3C2=O)C(=O)N1
Yield: 122.6 %

Procedure:
1.54 g thieno(3,4-c)furan-1,3-dione and 1.42 g of 3-aminopiperidine-2,6-dione trifluoroacetic acid were dissolved in 15 mL of acetic acid. The reaction mixture was refluxed overnight, cooled, and evaporated to remove the solvent. The residue was dissolved in 20 mL anhydrous THF, and 2 g of CDI, and a catalytic quantity of DMAP were added. The reaction mixture was refluxed for 6 h until a large amount of white solid precipitated. The solid was cooled and filtered to yield 1.9 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:22]([CH3:25])([O-:24])=[O:23]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[CH:25][N+:22]([O-:24])=[O:23]
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)c([N+](=O)[O-])c(OC)c1O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=C[N+](=O)[O-])c([N+](=O)[O-])c(OC)c1O
Yield: 58.5 %

Procedure:
A suspension of 20 g (0.088 mole) of 3,5-dimethoxy-4-hydroxy-2-nitrobenzaldehyde and 21 g (0.27 mole) of dry ammonium acetate in 400 cm3 of acetic anhydride and 15.8 g (0.26 mole) of nitromethane is heated under reflux for 2 hours. The reaction mixture is cooled, then the precipitate is filtered off. After washing with water, recrystallization from an ethanol-water mixture and drying under vacuum, 13.9 g of the desired product is obtained in the form of orangish-yellow crystals (yield=58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14].[CH:15](OC)(OC)OC>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15]
Reactant: Nc1cnccc1-c1ccccc1Cl
Reactant: COC(OC)OC
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of 14.9 g (72.8 mmol) 4-(2-chloro-phenyl)-pyridin-3-ylamine in 80 ml trimethyl orthoformate and 5 drops trifluoroacetic acid was heated for 2.5 h at 130° C. The reaction mixture was evaporated and dried in vacuo for 30 min. The residual oil was dissolved in 130 ml tetrahydrofuran and 220 ml (220 mmol) of 1 M borane-tetrahydrofuran complex were added dropwise under ice cooling. After stirring overnight at room temperature, the reaction mixture was evaporated, cooled to 0° C. and 130 ml 5 N hydrochloric acid solution in ethanol were added carefully. The solution was refluxed for 1 h, cooled to room temperature again and crushed ice was added. The aqueous phase was washed with three 100 ml portions diethyl ether and the organic layers were extracted with 100 ml 1 N hydrochloric acid solution. The combined aqueous layers were adjusted to pH 8-9 by addition of concentrated sodium hydroxide solution and were extracted with three 500 ml portions ethyl acetate. The combined organic extracts were dried (magnesium sulfate), evaporated and the solid residue was recrystallized from hexane/ethyl acetate to give 12.3 g (77%) of the title compound as white crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[C:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:10][C:9]=2[Br:19])[C:3]1=[O:20].[C:21]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]2[C:32]([CH:33]=O)=[CH:31][N:30]=[CH:29]2)=[CH:25][C:24]=1[F:37])#[N:22].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[Br:19][C:9]1[CH:10]=[CH:11][C:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=1[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:33][C:32]2[N:28]([CH2:27][C:26]3[CH:35]=[CH:36][C:23]([C:21]#[N:22])=[C:24]([F:37])[CH:25]=3)[CH:29]=[N:30][CH:31]=2)[C:3]1=[O:20]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: CS(=O)(=O)Oc1ccc(Br)c(CN2CCC(N)C2=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)Oc1ccc(Br)c(CN2CCC(NCc3cncn3Cc3ccc(C#N)c(F)c3)C2=O)c1
Reaction time: 0.5 h

Procedure:
3-Amino-1-(2-bromo-5-methanesulfonyloxybenzyl)-2-oxopyrrolidine, as described above in Step E, (640 mg, 1.12 mmol), 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described above in Example 1, Step G, (333 mg, 1.45 mmol) were stirred in MeOH (8 mL) and the solution was acidified to pH≈5 to 6, as judged by wetted pH indicator paper, with acetic acid. Stirring was continued for 30 min, then NaCNBH3 (118 mg, 1.88 mmol) was added. Stirring was continued for 18 hours, then the reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (20 mL). The aqueous layer was extracted further with EtOAc (2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2—1% to 5% MeOH, to yield the desired product.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]2)=[CH:14][N:13]=1>CN(C=O)C.CCOC(C)=O>[CH2:3]([S:10][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:26])=[O:27])[CH2:21][CH2:20]2)=[CH:14][N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: CS(=O)(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC(Oc2ccc(SCc3ccccc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
A suspension of NaH (60% dispersion in mineral oil, 413 mg, 10.32 mmol) in dry DMF (12 mL) at 0° C. was treated dropwise with benzyl mercaptan (1.21 mL, 10.32 mmol). After the addition the mixture was stirred at room temperature for 15 minutes. 2-Chloro-5-(1-methanesulfonyl-piperidin-4-yloxy)-pyridine (1.00 g, 3.44 mmol) was added and the mixture stirred at room temperature for 18 hours, heated at 80° C. for a further 8 hours and allowed to cool overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purified by silica gel column chromatography (30-50% EtOAc in cyclohexane) to give 2-benzylsulfanyl-5-(1-methanesulfonyl-piperidin-4-yloxy)-pyridine (659 mg, 51%). 1H NMR (300 MHz, CDCl3) δ 8.20 (br s, 1H), 7.40-7.34 (m, 2H), 7.32-7.18 (s, 4H), 7.14-7.05 (m, 2H), 4.52-4.43 (m, 1H), 4.39 (s, 2H), 3.36 (t, J=5.6 Hz, 4H), 2.82 (s, 3H), 2.08-1.91 (m, 4H). LCMS (m/z, Method A) ES+ 379.1 [M+1]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([N:10]1[C:14]([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[CH:13][C:12]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[N:11]1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl.C(=O)([O-])O.[Na+]>[C:6]([N:10]1[C:14]([NH:15][C:16](=[O:29])[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[CH:13][C:12]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[N:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(N4CCNCC4)cc3)n(C(C)(C)C)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n(C(C)(C)C)n2)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Methanesulphonyl chloride (0.042 mL, 0.55 mmol) was added at 0° C. to a solution of N-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(piperazin-1-yl)benzamide (0.231 g, 0.5 mmol) and N,N-diethylethanamine (0.077 mL, 0.55 mmol) in DCM (4 mL). The resulting solution was stirred at 20° C. for 1 h. The reaction mixture was diluted with saturated sodium hydrogen carbonate (10 ml) filtered and the solid washed with DCM (2×10 ml). The organic layers were combined and washed with water (20 ml) and saturated brine (20 ml). The organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by silica column chromatography, eluting with a gradient of 0-5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(4-(methylsulfonyl)piperazin-1-yl)benzamide (0.255 g, 94%) as a white solid. MS: m/z=540 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:14][CH:13]=[CH2:12])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(Br)ccc1O
Reaction time: 72 h
Yield: 90.7 %

Procedure:
A mixture of 5-bromosalicylic acid (10 g, 46 mmol), allyl bromide (6.12 g, 51 mmol) and sodium bicarbonate (4.65 g, 55 mmol) in 50 ml of DMF was stirred under a drying tube for 72 hr. The reaction mixture was poured into water, extracted with ethyl acetate. and the organic layer dried over MgSO4. Concentration under vacuum gave 10.73 g (91%) of product (1-Scheme 2) with the expected NMR.
Reaction SMILES: [CH2:1]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH:12](C(OC)=O)[C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5].C(C1C(=O)CCC1CC(O)=O)CCCC>O>[CH2:1]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1C(=O)CCC1C(C(=O)OC)C(=O)OC
Agent: CCCCCC1C(=O)CCC1CC(=O)O
Solvent: O
Product: CCCCCC1C(=O)CCC1CC(=O)OC
Reaction time: 16 h
Yield: 97.4 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a supply unit, a thermometer and a rectifier was charged with 600 g of raw material containing 545 g (1.92 mol) of dimethyl 2-pentyl-3-oxo-cyclopentylmalonate produced in the same manner as in Production Example 1 and the raw material was heated to 180° C. with stirring under normal pressure. Then, the supply of water to the bottom of the reactor was started. During the supply of water, the supply rate of water was adjusted to 6 g/h from the start of the supply to the 2nd hour, to 3 g/h from the 2nd hour to the 8th hour and to 1.2 g/h after the 8th hour with measuring the content of water in the reaction solution by a Karl Fischer's coulometric titration (instrument: Trace-water measuring device AQ-7, manufactured by HIRANUMA SANGYO Co., Ltd.) such that the content of water was limited to 0.4% by weight or less. Then, the reaction was completed for 16 hours from the start of the supply of water. The maximum water concentration in the reaction solution was 0.21% by weight. During the reaction, the difference (X−Y) between the integrating molar number X (excluding distilled water content) of the water to be supplied and the molar number Y of the water reacted with dimethyl 2-pentyl-3-oxo-cyclopentylmalonate was 14.8% at a maximum based on the molar number of the charged dimethyl 2-pentyl-3-oxo-cyclopentylmalonate. It was found that the reaction product contained 423 g (1.87 mol, yield: 97.3%) of methyl 2-pentyl-3-oxo-cyclopentylacetate and 10.8 g (0.051 mol) of 2-pentyl-3-oxo-cyclopentylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]([N:15]=[C:16]=S)([CH3:14])[CH3:13].C1(N=C=NCCN2CCOCC2)CCCCC1.CC1C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[CH:12]([NH:15][C:16]1[NH:10][C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=2[N:11]=1)([CH3:14])[CH3:13]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1N
Reactant: CC(C)N=C=S
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(Cl)c(Cl)c(Cl)cc2[nH]1
Yield: 70.3 %

Procedure:
3,4,5-Trichloro-1,2-phenylenediamine (3.12 g, 14.8 mmol), isopropyl isothiocyanate (1.62 g, 16.0 mmol), cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (8.4 g, 19.9 mmol), and pyridine (50 mL) were used according to general procedure II. The product was crystallize from 1,4-dioxane to give 2.9 g (72%) of a tan solid MS (CI): m/z 276 (M+1). Anal. Calcd for C10H10Cl3N3-(0.10 C4H8O2): C, 43.47; H, 3.79; N, 14.62. Found: C, 43.70; H, 3.89; N, 14.43.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:41]1[CH:40]=[C:39]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]4[CH2:23][CH2:22][N:21]([CH:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[C:20]4=[O:30])=[O:18])=[N:13][C:14]=3[CH3:15])[CH:5]=[CH:4][N:3]=2)[CH:43]=[N:42]1
Reactant: Cc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(Cl)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(-c2cn[nH]c2)c1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A solution of Example C3 (0.12 g, 0.28 mmol) in dioxane (4 mL) was sparged with Ar, treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.08 g, 0.42 mmol), a solution of K2CO3 (0.077 g, 0.55 mmol) in water (1 mL) and Pd(PPh3)4 (0.032 g, 0.03 mmol) and heated at 90° C. overnight. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (72 mg, 56%). 1H NMR (400 MHz, DMSO-d6): δ 13.05 (br s, 1 H), 10.89 (s, 1 H), 8.35 (d, J=5.7 Hz, 1 H), 8.31 (brs, 1 H), 8.03 (s, 1 H), 7.89 (d, J=8.8 Hz, 1 H), 7.61 (d, J=8.8 Hz, 1 H), 7.28 (d, J=2.4 Hz, 1 H), 6.56 (dd, J=5.7, 2.4 Hz, 1 H), 3.95-3.77 (m, 5 H), 3.43-3.39 (m, 4 H), 2.24 (s, 3 H), 1.71-1.70 (m, 2 H), 1.60 (d, J=12.4 Hz, 2 H); MS (ESI) m/z: 464.2 (M+H+).
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH2:22]([O:24][C:25]([C:27]1[C:28]2[N:29]=[CH:30][CH:31]=[N:32][C:33]=2[C:34]([C:37]2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=2)=[CH:35][CH:36]=1)=[O:26])[CH3:23].C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O>[CH2:22]([O:24][C:25]([C:27]1[C:28]2[N:29]=[CH:30][CH:31]=[N:32][C:33]=2[C:34]([C:37]2[CH:38]=[C:39]([O:45][CH3:46])[CH:40]=[C:41]([O:43][CH3:44])[C:42]=2[F:21])=[CH:35][CH:36]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2nccnc12
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2nccnc12
Reaction time: 12 h
Yield: 46.8 %

Procedure:
SelectFluor (105 mg, 0.30 mmol) was added to a cold (−5° C.) solution of 8-(3,5-dimethoxyphenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 115.1) (100 mg, 0.30 mmol) in CH3CN (2 mL), under an argon atmosphere. The reaction mixture was allowed to warm to it over 6 h and stirred at that temperature for additional 12 h and diluted in EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:2) to provide 50 mg of the title compound as an off-white solid. Title compound: ESI-MS: 357.2 [M+H]+; tR=4.58 min (System 1); TLC: Rf=0.24 (Hex/EtOAc, 3:2).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]2[C:8](=[O:20])[C:9]3[NH:10][CH:11]=[N:12][C:13]=3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:6]2=[N:5][N:4]=1.[Br:21]N1C(=O)CCC1=O>C1COCC1.O>[Br:21][C:11]1[NH:10][C:9]2[C:8](=[O:20])[N:7]3[C:3]([S:2][CH3:1])=[N:4][N:5]=[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]=2[N:12]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(SC)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(SC)nnc12

Procedure:
A solution of 3-(methylthio)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (111 mg, 0.380 mmol), N-bromosuccinimide (81.1 mg, 0.456 mmol) in THF (3 ml) was stirred at 70° C. for 3 hours. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by Prep LCMS to yield the desired product. LCMS calculated for: C12H16BrN6OS (M+H) 371.0. Found: 371.0, 373.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:15])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.CCN(CC)CC.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:15])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ncc(N2CCNCC2)nc1C(=O)Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)Nc3ccccn3)n2)CC1
Reaction time: 2 h
Yield: 100 %

Procedure:
3-amino-6-piperazin-1-yl-N-(2-pyridyl)pyrazine-2-carboxamide (100 mg, 0.1896 mmol) was dissolved in DCM (5 mL) and treated with Et3N (57.56 mg, 79.28 μL, 0.5688 mmol) followed by ethanesulfonyl chloride (26.82 mg, 19.76 μL, 0.2086 mmol). The reaction mixture was allowed to stir for 2 hours and then diluted with dichloromethane and washed with water. The aqueous layer was extracted further with dichloromethane and the organics washed with saturated aqueous NaHCO3, dried and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (0-5% MeOH/DCM) to afford the title compound (74.2 mg, 37% Yield). 1H NMR (400.0 MHz, DMSO) d 1.24 (t, J=7.3 Hz, 3H), 3.13 (q, J=7.4 Hz, 2H), 3.34-3.38 (m, 4H), 3.52-3.54 (m, 4H), 7.04 (s, 2H), 7.18-7.21 (m, 1H), 7.88 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.38 (d, J=3.2 Hz, 2H) and 10.08 (s, 1H) ppm; MS (ES+) 392.0
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH2:16]=[CH:17][CH:18]=[CH2:19].[N+](C1C2C(=CC=CC=2)C=CC=1)([O-])=O>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]1[CH:8]([C:9]2=[O:14])[CH2:19][CH:18]=[CH:17][CH2:16]1)([O-:3])=[O:2]
Reactant: C=CC=C
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=[N+]([O-])c1cccc2ccccc12
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12

Procedure:
The 5-nitro-1,4-naphthoquinone introduced into the reactor 8 for the Diels-Alder reaction is subjected to Diels-Alder reaction with 1,3-butadiene introduced from the tank 9 via a line 26 at a suitable temperature under a suitable pressure in the presence of a suitable solvent introduced from the tank 7 via a line 27. Since the unreacted 1-nitronaphthalene present in the reaction solution does not react with 1,3-butadiene, no side reaction occurs. The reaction mixture is filtered in the filter 10. The crystals of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone formed by the Diels-Alder reaction are sent to the reactor 12 for the reducing reaction via a line 30, and reduced with a suitable reducing agent introduced from the tank 13 via a line 33 to form 1-aminoanthraquinone. Meanwhile, the filtrate is sent to the separation tower 11 via a line 29 and separated into the solvent and 1-nitronaphthalene by, for example, distillation. The solvent is sent to the tank 7 via a line 32, and 1-nitronaphthalene is recycled to the tank 4 via line 31 for re-use.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-:32].[Na+].Cl>CC(C)=O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([OH:4])=[O:32])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Reaction time: 20 h

Procedure:
To a stirred solution of 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone (0.20 mmol) in acetone (1.2 mL) was added 0.15 mL of 2.5 N sodium hydroxide. After stirring for 20 hours the mixture was acidified with 2.0 N hydrochloric acid, extracted into ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. The solution was then evaporated and the residue purified by trituration with diethylether. The solid (0.066 g, 83%) was collected and dried, m.p. 168° C. MS [(+)ESI, m/z]: 395 [M+H]+ Anal. Calcd for C21H17CIN2O4: C, 63.56; H, 4.32; N, 7.06. Found: C, 63.66; H, 4.48; N, 6.86