Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][NH:14][C:13](=[O:18])[C:12]=3[CH:19]=2)=[CH:4][C:3]1=[O:20].[H-].[Na+].Cl.Cl[CH2:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C=O)C>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([CH2:25][C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:13](=[O:18])[C:12]=3[CH:19]=2)=[CH:4][C:3]1=[O:20]
Reactant: ClCc1ncccn1
Reactant: Cn1ccc(-c2ccc3c(c2)C(=O)NCCO3)cc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ccc3c(c2)C(=O)N(Cc2ncccn2)CCO3)cc1=O
Temperature: 25 °C

Procedure:
7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (50 mg, 0.185 mmol) was dissolved in DMF (3 mL) and cooled down in a ice/water bath and treated with sodium hydride (60% dispersion) (17 mg, 0.41 mmol) portion wise. After 10 min a solution of 2-(chloromethyl)pyrimidine hydrochloride (37 mg, 0.22 mmol) in DMF (2 mL) was added and the reaction mixture was warmed up to room temperature and quenched with 6 mL of water after it was complete. The reaction mixture was extracted with EtOAc and water and the organic phase was dried, evaporated and purified by silica gel chromatography (95% DCM/MeOH) and then purified by reverse phase chromatography to afford 7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[CH:21]([OH:24])([CH3:23])[CH3:22].O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:24][CH:21]([CH3:23])[CH3:22])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.1 %

Procedure:
To a stirred solution of 4-chloro-3-nitrobenzoyl chloride (20.5 g) in ethyl acetate (80 cm3) was added a solution of triethylamine (10.1 g) and i-propylalcohol (6 g) in ethylacetate (40 cm3) over 15 mins causing a slight exotherm. The reaction was stirred at the ambient temperature for a further 3.5 hours and then poured into water. The layers were separated and the aqueous layer was extracted with ethyl acetate and the combined ethyl acetate layers were washed with 10% HCl, brine and dried with sodium sulphate. Filtration and evaporation gave iso-propyl 4-chloro-3-nitrobenzoate as a yellow solid (22.5 g). 1H nmr (CDCl3) d: 8.49 (1H, d), 8.17 (1H, dd), 7.64 (1H, d), 5.29 (1H, septet), 1.40 (6H, d). Mpt 61°-62° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N1C=CC=CC=1.[OH2:30]>>[C:15]([O:22][C:10]1[CH:11]=[CH:12][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1)(=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O
Reactant: Oc1ccccc1C1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Oc1ccc(C2CCCCC2)cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
17.6 g (100 mmol) of cyclohexylphenol and 19 g (106 mmol) of nicotinic acid chloride hydrochloride was mixed with 250 ml of dry pyridine and kept at 40° C. for 4 hours. Subsequently, the mixture was cooled in the ice bath, and water added in portions. After addition of 10 ml of water a clear solution was obtained. Water (50 ml) was admixed until strong turbidity appeared. After stirring the mixture for a longer period of time the product crystallized in the ice bath. The precipitate was sucked off, freed from pyridine by washing with water and dried. A second fraction was obtained from the filtrate by further adding water (60 ml).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[C:8]([CH:15]2[O:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)CCC.Br[C:30]1[N:34]([CH3:35])[N:33]=[CH:32][N:31]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[O:20]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[C:8]1[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=[C:6]([C:30]2[N:34]([CH3:35])[N:33]=[CH:32][N:31]=2)[CH:7]=1
Reactant: Cn1ncnc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C2OCCCO2)c2occc2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1ncnc1-c1cc(C2OCCCO2)c2occc2c1
Yield: 35.2 %

Procedure:
A mixture of tributyl-(7-[1,3]dioxan-2-ylbenzofuran-5-yl)stannane (839 mg), 5-bromo-1-methyl-1H-[1,2,4]triazole (396 mg), bis(triphenylphosphine)palladium (II) chloride (59 mg) in dry toluene (10 ml) was heated at reflux for 42 h. The cooled solution was then filtered through Hyflo and the filtrate washed with 10% potassium fluoride solution (30 ml). The organic layer was washed with brine (30 ml), dried, and evaporated in vacuo to give a yellow oil. The crude material was purified by FCC eluting with hexane:ethyl acetate (1:1→1:3) to give the title compound as a yellow oil (171 mg,).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH3:21])=[N:15][C:16]=2Cl.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH3:21])=[N:15][C:16]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: Cc1nc(Cl)c2ncn(-c3ccc(C(C)C)cc3Br)c2n1
Product: Cc1nc(N2CCOCC2)c2ncn(-c3ccc(C(C)C)cc3Br)c2n1

Procedure:
9[2-bromo-4(2-propyl)phenyl]-2-methyl-6-chloropurine (1.3 g) and morpholine (10 mL) were combined under nitrogen and refluxed for 6 hrs. The reaction mixture was concentrated by rotovap and the residue was purified by flash chromatography (CH2Cl2 :MeOH, 50:1, silica) to yield a yellow solid (0.54 g). MS (M+H)+ 416, 418.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[H][H].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CS(C)=O.O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:21][C:20]1[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=1
Reactant: NCCCNc1ccccn1
Reactant: [H][H]
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NCCCN(Cc1ccc(Cl)cc1)c1ccccn1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
A mixture of sodium hydride (1.12 g) and 2-(3-amino-propylamino) pyridine (7.05 g) in DMSO (30 ml) was heated slowly to 85° C. under nitrogen. After the evolution of hydrogen had ceased the solution was cooled to room temperature and 4-chlorobenzyl chloride (5.95 ml) in DMSO (10 ml) added dropwise keeping the temperature below 30° C. After standing for 72 hr, water (300 ml) was added and the mixture extracted with ether. The extract was washed with water and 2N hydrochloric acid. The pH of the acid washing was raised to 6 and extracted with ether. The pH was raised further to 14 and extracted again with ether. After drying (MgSO4) and stripping, the final ether extract gave 2-[N-(3-aminopropyl)-N-(4-chlorobenzyl)amino]pyridine (7.43 g) as an oil, bp 160° C. 0.04 mm Hg. (ii) 2-[N-(3-aminopropyl)-N-(4-chlorobenzyl)amino]pyridine (1.25 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.08 g) were heated together under reflux in pyridine (10ml) for 20 hr. On cooling, the mixture was stripped, the residue triturated with wet ether and recrystallised from isopropanol/water to give 2-[3-[N-(4-chlorobenzyl)-N-pyrid-2-ylamino]propylamino]-5-(6-methyl-pyrid-3-ylmethyl) pyrimid-4-one 1H2O, 1.68 g (83%) mp 88°-92° C.
Reaction SMILES: C(OC)(=O)C1C=CC(C([O-])=O)=CC=1.[K+:14].[C:15]([O:30]CCCC)(=[O:29])[C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:18][CH:17]=1.[OH-].[K+].C1(C)C=CC=CC=1>C(O)CCC>[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:21])[C:19]1[CH:27]=[CH:28][C:16]([C:15]([O-:30])=[O:29])=[CH:17][CH:18]=1.[K+:14]
Reactant: CCCCOC(=O)c1ccc(C(=O)OCCCC)cc1
Agent: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc(C(=O)[O-])cc1
Yield: 96 %

Procedure:
This compound was prepared by the procedure described for potassium monomethyl terephthalate. Typical reagent levels were as follows: dibutyl terephthalate (10.0 g, 0.036 mole), potassium hydroxide (2.1 g, 0.036 mole), 50 ml of toluene and 20 ml of 1-butanol. After workup 9.4 g was recovered which represented a 96% yield.
Reaction SMILES: [H-].[Na+].CS(C)=O.Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[Cl:16].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>O>[Cl:16][C:10]1[CH:11]=[C:12]([O:15][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml). The mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-3-chlorophenol hydrochloride (1.61 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue. The precipitated crystal was collected by suction filtration to give 0.89 g (yield 60%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:11]([C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)#[CH:12]
Reactant: C[Si](C)(C)C#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Nitro-4-(trimethylsilylethinyl)aniline (3.96 g; 16.9 mmol; 1 eq.) was dissolved in MeOH (50 ml) and CH2Cl2 (50 ml) and treated with K2CO3 (9.33 g; 67.6 mmol; 4 eq.). After stirring at room temperature for 5 h, the mixture was diluted with water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×100 ml). The combined organic layers were dried over Na2SO4, evaporated and the residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 2.06 g (75.1%); MS m/z: 163.4 [M+H]+
Reaction SMILES: CS(O[CH2:6][C:7]1([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)(=O)=O.[C-:20]#[N:21].[K+]>CN(C)C=O.O.CCOCC>[CH2:13]([O:12][CH2:11][C:7]1([CH2:6][C:20]#[N:21])[CH2:10][CH2:9][CH2:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)OCC1(COCc2ccccc2)CCC1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC1(COCc2ccccc2)CCC1
Temperature: 130 °C
Yield: 63 %

Procedure:
To a solution of 16.75 g (59.0 mmol) of {1-[(benzyloxy)methyl]cyclobutyl}methyl methanesulfonate in 150 mL of N,N-dimethylformamide and 15 mL of water was added 4.97 g (88.5 mmol) of potassium cyanide and the contents heated at 130° C. for 5 h. The reaction mixture was cooled, diluted with ether and water, and the layers separated. The organic phase was dried using magnesium sulfate and concentrated under vacuum to afford the crude product, which was purified by silica gel chromatography using ethyl acetate/hexane (1:3) as the eluent to afford 8.0 g (88%) of {1-[(benzyloxy)methyl]cyclobutyl}acetonitrile as a colorless oil. 1H NMR (300 MHz, CDCl3). 1H NMR (300 MHz, CDCl3) δ 7.43-7.29 (m, 5H), 4.59 (s, 2H), 3.5 (s, 2H), 2.6 (s, 2H), 2.08-1.92 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27].CO.[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][S:28]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([F:20])[CH:22]=2)(=[O:29])=[O:30])[C:3]([C:9]([C:11]2[C:12]3[CH:19]=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][CH:16]=2)=[O:10])=[N:4][CH:5]=1
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccnc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc3[nH]ccc23)cc1F

Procedure:
Prepared from 18 mg (0.066 mmol) of (3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanone and 48 mg (0.25 mmol) of 3-fluoro-4-methyl-benzenesulfonyl chloride in 0.10 mL pyridine using procedure x. After the sulfonylation was complete, 2 mL methanol, 0.5 mL water and 32 mg sodium hydroxide were used. Yield: 20 mg of a yellow solid. LC-MSD, m/z for C20H14ClFN4O3S [M+H]+=445.0, 447.0.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)[CH3:2].[Mg:12].[S:13](=[O:15])=[O:14]>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:13]([O-:15])=[O:14])[CH3:2].[Mg+2:12].[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:13]([O-:15])=[O:14])[CH3:2]
Reactant: [Mg]
Reactant: CCOc1ccccc1CCl
Reactant: O=S=O
Solvent: CCOCC
Product: CCOc1ccccc1CS(=O)[O-]
Product: [Mg+2]
Reaction time: 0.5 h

Procedure:
A Grignard solution of 30.5 of 2-ethoxybenzyl chloride and 6.1 g of magnesium shavings in 250 ml of diethyl ether is added dropwise at -60° C. to -70° C. to 50 ml of sulfur dioxide. Stirring is continued for 0.5 hour at -70° C., the mixture is allowed to come to room temperature, and the salt magnesium 2-ethoxybenzylsulfinate which has formed (47 g, melting point: 134°-139° C., decomposition) is filtered off with suction. The sulfinate salt is dissolved in 900 ml of water and 16.4 g of anhydrous sodium acetate. To this are added 22.7 g of hydroxylamine-O-sulfonic acid at room temperature with stirring. After the mixture has been stirred for 12 hours, the product is filtered off with suction and dried in vacuo. This give 23.9 g of 2-ethoxybenzylsulfonamide of melting point: 92°-93° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:7]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[C:8]=1[Br:9].C(O)(=O)C.O[CH2:29][NH:30][C:31](=[O:33])[CH3:32]>O1CCCC1>[Br:3][C:4]1[N:5]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:7]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[C:8]=1[Br:9]
Reactant: O=S(=O)(c1c(-c2ccc(Cl)cc2)[nH]c(Br)c1Br)C(F)(F)F
Reactant: CC(=O)NCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)NCn1c(Br)c(Br)c(S(=O)(=O)C(F)(F)F)c1-c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
A mixture of sodium hydride (0.5 g, 60%, 0.0125 mol) and tetrahydrofuran is treated with 2,3-dibromo-5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrole (4.67 g, 0.01 mol), stirred for 15 minutes and treated with a solution of N-(hydroxymethyl)acetamide acetate (ester) (1.64 g, 0.0125 mol) in tetrahydrofuran. The reaction mixture is heated at reflux for 18 hours, concentrated in vacuo and poured into a water/ether mixture. The organic phase is separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a white solid (4.56 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:5]2=[N:6][CH:7]=1.[Cl-].C(C1C=CC=C(C(C)C)[C:30]=1[C:38]1NC=[C:40]([C:43]2C(C(C)C)=CC=CC=2C(C)C)[NH+:39]=1)(C)C.CC(C)([O-:58])C.[K+]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[CH3:24][O:23][CH2:22][CH2:21][O:20][CH2:19][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([N:39]3[CH2:40][CH2:43][O:58][CH2:30][CH2:38]3)[CH:3]=[C:4]2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:9]1
Reactant: CC(C)c1cccc(C(C)C)c1-c1c[nH]c(-c2c(C(C)C)cccc2C(C)C)[nH+]1
Reactant: CC(C)(C)[O-]
Reactant: COCCOCn1cc(-c2ccccc2OC)c2cc(Br)cnc21
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [K+]
Solvent: N#Cc1ccccc1
Product: COCCOCn1cc(-c2ccccc2OC)c2cc(N3CCOCC3)cnc21
Temperature: 120 °C
Yield: 656.9 %

Procedure:
180 mg (0.5 mmol) of 5-bromo-1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine, 10 mg of bis(benzonitrile)palladium(II)-chloride, 11 mg of 2,5-bis-(2,6-di-iso-propylphenyl)imidazolium chloride, and 65 mg of potassium-tert-butoxide were placed in a Smith® vial. The vial was flushed with nitrogen and 3 ml of anhydrous 1,4-dioxane and 70 μl of morpholine were added. The resulting mixture was heated to 120° C. for 14 h. The mixture was cooled to room temperature, adsorbed onto silica gel, and purified by flash chromatorgraphy on silica gel using a gradient of ethyl acetate in hexanes to afford 65 mg (0.17 mmol, 33% yield) of 1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine as a colorless oil. 1H-NMR (CDCl3): δ 8.17 (d, J=2.8 Hz, 1H), 7.63 (s, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.54 (dd, J=1.6 Hz, 7.4 Hz, 1H), 7.31 (ddd, J=1.6 Hz, 7.4 Hz, 9 Hz, 1H), 7.07 (ddd, J=1.1 Hz, 7.4 Hz, 7.4 Hz, 1H), 7.03 (d(m), J=8.3 Hz, 1H), 5.71 (s, 2H), 3.87 (s, 3H), 3.68 (m, 2H), 3.49 (m, 2H), 3.35 (s, 3H); MS: m/z 398 [MH+].
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[N:10]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:8]=2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>O1CCCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:14]([NH:13][C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:3]3)[CH:8]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:10]=2)[CH3:15])=[CH:17][CH:18]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCC(N)C2)n1)c1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCC(NS(C)(=O)=O)C2)n1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
110 mg of 6-(3-aminopyrrolidin-1-yl)-N2-[(S)-1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 59) was dissolved in 3 ml of tetrahydrofuran, and 91 μl of N,N-diisopropylethylamine and 21 μl of methanesulfonyl chloride were added at 0° C., and the mixture was stirred at 0° C. for 1 hour. Water was added to the reaction solution, and then the reaction solution was subjected to extraction with ethyl acetate, and the organic layer was washed with water and brine in turn, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 92 mg of N-(1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-yl)methanesulfonamide as a pale yellow amorphous solid. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 70 mg of the objective compound as pale yellow powder.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[SH:11][CH:12]([CH3:18])[C:13](OCC)=[O:14].C(=O)([O-])[O-].[NH4+:23].[NH4+]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:1]1[NH:23][C:13](=[O:14])[CH:12]([CH3:18])[S:11]1
Reactant: [NH4+]
Reactant: CCOC(=O)C(C)S
Reactant: COc1ccccc1C=O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccccc1C1NC(=O)C(C)S1
Temperature: 110 °C
Yield: 94 %

Procedure:
A mixture of 13.6 g of o-anisaldehyde, 13.4 g of ethyl 2-mercaptopropionate and 6 g of ammonium carbonate in 250 ml of toluene was refluxed at 110° C. for 2 hours in a flask provided with a Dean-Stark apparatus while removing the distilled water. The crystals which separated out after leaving the reaction mixture for a night were collected by filtering and recrystallized from hot benzene to obtain the object, colourless prisms melting at 187° to 187.5° C. in an amount of 21 g corresponding to a yield of 94%.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>ClCCl>[F:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][NH:14][C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])=[CH:4][CH:3]=1
Reactant: NCCCc1ccc(F)c2c1CCO2
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCc1ccc(F)c2c1CCO2)C1CC1
Reaction time: 0.33 h
Yield: 10.4 %

Procedure:
A mixture of 3-(7-fluoro-2,3-dihydro-benzofuran-4-yl)-propylamine (114 mg), triethylamine (0.089 ml), dichloromethane (5 ml) and cyclopropanecarbonyl chloride (67 mg) was stirred in ice for 20 minutes and stirring continued at room temperature overnight. The mixture was partitioned between 2N hydrochloric acid and dichloromethane and the organic phase washed with 8% sodium bicarbonate and evaporated. Purification of the residue by preparative hplc gave the title compound as a white solid (16 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]3)[C:7]=2[CH:29]=1)#[N:2].I([O-])(=O)(=O)=[O:31].[Na+].COC1C=CC2OCC(=O)N(CCN3CCC(NC(=O)OC(C)(C)C)CC3=O)C=2C=1>O.[Ru](=O)=O.C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:19][C:20]3=[O:31])[C:7]=2[CH:29]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(C#N)cc32)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1=O)C(=O)CO2
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(C#N)cc32)C(=O)C1

Procedure:
tert-Butyl {1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 59, 835 mg, 2.1 mmol) was reacted with sodium periodate (2.8 g, 13.1 mmol) and ruthenium (IV) oxide hydrate (30 mg, 20.1 mmol) as described for Intermediate 115 for 16 hours, except, chloroform was used for aqueous workup. The product was obtained as a colorless solid, 230 mg (27%).
Reaction SMILES: C([O:8][C:9](=[O:22])[C@H](CCCNC(=N)N)N[N+]([O-])=O)C1C=CC=CC=1.N[C@H](C(O)=O)C.C([O:36][C:37](=[O:59])[C@H:38]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[NH:58])[NH2:57])[N:39]([N+]([O-])=O)[C:40](=[O:48])[CH:41]([CH3:47])[CH2:42]C(OC)=O)C1C=CC=CC=1.COC(CC(C)C(N[C@H](C(O)=O)CCCNC(=N)N)=O)=O>>[C:9]([CH:52]([CH2:53][CH2:54][NH:55][C:56](=[NH:58])[NH2:57])[C@@H:38]([C:37]([OH:36])=[O:59])[NH:39][C:40](=[O:48])[CH:41]([CH3:42])[CH3:47])([OH:22])=[O:8]
Reactant: COC(=O)CC(C)C(=O)N([C@@H](CCCNC(=N)N)C(=O)OCc1ccccc1)[N+](=O)[O-]
Reactant: N=C(N)NCCC[C@H](N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: COC(=O)CC(C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: C[C@H](N)C(=O)O
Product: CC(C)C(=O)N[C@H](C(=O)O)C(CCNC(=N)N)C(=O)O

Procedure:
By substituting nitro-L-arginine benzyl ester for the L-alanine in the procedure of Example 1, and then treating the product by the procedures of Examples 2 and 3, Nα -(3-methoxycarbonyl-2-methylpropanoyl)-nitro-L-arginine benzyl ester, Nα -(3-methoxycarbonyl-2-methylpropanoyl)-L-arginine and Nα -(3-carboxy-2-methylpropanoyl-L-arginine are obtained.