Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH:12]([O-:14])=[O:13].[NH4+:15]>[Ir].CO>[CH:8]1[CH:7]=[CH:6][C:5]([CH:4]([NH2:15])[C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: O=C[O-]
Reactant: O=COC(=O)c1ccccc1
Reactant: [NH4+]
Agent: [Ir]
Solvent: CO
Product: NC(C(=O)O)c1ccccc1
Temperature: 60 °C
Yield: 95 %

Procedure:
751 mg (5.0 mmol) of benzoyl formate (MW: 150.13), 946 mg (15.0 mmol) of ammonium formate (MW: 63.06), and 5.90 mg (0.01 mmol, S/C=500) of the iridium catalyst Ir-7 (MW: 590.13) were introduced in a 20-mL Schlenk tube and subjected to argon-gas replacement. 5 mL of dehydrated methanol was added and the mixture was stirred while heating at 60° C. for 1.5 hr. After distillation of the solvent, a crystal was collected by filtration, washed with methanol, dried under reduced pressure to give 718 mg of DL-2-phenylglycine (95% yield).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[Br:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1.CS(C)=O.C(OCC)(=O)C>O>[Br:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:27]=1
Reactant: Brc1c[nH]cn1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cnc(Br)c3)cc2c1=O
Temperature: 120 °C
Yield: 21.7 %

Procedure:
A mixture of 20 mg (0.062 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 56 mg (0.372 mmol) of 4-bromo-1H-imidazole and 0.1 ml of DMSO is heated to 120° C. for 16 hours. After cooling to room temperature, the reaction mixture is distributed between ethyl acetate and water, the organic phase is separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel using dichloro-methane-methanol (95:5) and the fractions containing the desired product are combined and evaporated yielding 6 mg (21%) of the title compound. MS (ES−): m/e=445 (M−).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH:10]=O)[CH2:5][CH2:4]1.[C-:12]#[N:13].[K+].[NH4+:15].[Cl-]>N.O>[NH2:15][CH:10]([CH2:9][CH:6]1[CH2:7][CH2:8][N:3]([O:2][CH3:1])[CH2:4][CH2:5]1)[C:12]#[N:13]
Reactant: [C-]#N
Reactant: [NH4+]
Reactant: CON1CCC(CC=O)CC1
Agent: N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CON1CCC(CC(N)C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(1-Methoxy-piperidin-4-yl)-acetaldehyde (1.7 g, 10.8 mmol) was added dropwise to a mixture of KCN (910 mg, 14 mmol) and NH4Cl (795 mg, 15 mmol) in 10 ml of 33% aqueous ammonia and 10 ml of water at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with 20 ml of water and extracted with CH2Cl2 three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel. Yield: 1.0 g of 2-amino-3-(1-methoxy-piperidin-4-yl)-propionitrile as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH:11]=O)[C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Br:1][C:2]1[CH:10]=[C:9]([CH:11]2[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH2:27][CH2:28][CH3:29])[NH:13][C:14]3=[N:15][NH:16][CH:17]=[C:18]23)[C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1cc(Br)cc2c1OCC2
Product: CCCC1=C(C(=O)OCC)C(c2cc(Br)cc3c2OCC3)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 5-bromo-2,3-dihydobenzo[b]furan-7-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12](SC)[NH:13][CH:14]=2)=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=2)[CH2:23][CH2:22]1>ClC(Cl)Cl>[OH2:17].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12]([NH:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28]4[N:32]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[C:31]5[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=5[N:29]=4)[CH2:23][CH2:22]3)[NH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CSc1nc(=O)c(Cc2ccc(Cl)cc2)c[nH]1
Solvent: ClC(Cl)Cl
Product: O
Product: O=c1nc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)[nH]cc1Cc1ccc(Cl)cc1
Temperature: 140 °C
Yield: 76.8 %

Procedure:
A mixture of 2.7 parts of 5-[(4-chlorophenyl)methyl]-2-(methylthio)-4(1H)-pyrimidinone and 3.67 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol -2-amine was stirred and heated for 4 hours at 140° C. The reaction mixture was cooled and taken up in trichloromethane. The solution was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 1,1'-oxybisethane, yielding 4.5 parts (76.8%) of 5-[(4-chlorophenyl)methyl]-2-[[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]amino]-4(1H)-pyrimidinone monohydrate; mp. 150.6°-158.7° C. (compound 85).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][C:27]1([CH3:33])[O:31][C:30](=[O:32])[NH:29][CH2:28]1>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:28][C:27]([CH3:33])([CH3:26])[O:31][C:30]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC1(C)CNC(=O)O1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3F)CC2)c(C)c1
Yield: 28.3 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (1 g) described in Preparation Example 100 and 5,5-dimethyloxazolidin-2-one (437 mg) described in Preparation Example 43, the title compound (307 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][N:3]=1.Cl.ClC1C=C(N2C(=O)C=C(OC3CCNCC3)C(C#N)=N2)C=CC=1Cl.ClC1N=CC(CCC)=CN=1.Cl.[C:47]([C:49]1[CH:54]=[CH:53][C:52]([N:55]2[C:60](=[O:61])[CH:59]=[C:58]([O:62][CH:63]3[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]3)[C:57]([C:69]#[N:70])=[N:56]2)=[CH:51][C:50]=1[F:71])#[N:48]>>[C:47]([C:49]1[CH:54]=[CH:53][C:52]([N:55]2[C:60](=[O:61])[CH:59]=[C:58]([O:62][CH:63]3[CH2:64][CH2:65][N:66]([C:2]4[N:3]=[CH:4][C:5]([CH2:8][CH2:10][CH3:9])=[CH:6][N:7]=4)[CH2:67][CH2:68]3)[C:57]([C:69]#[N:70])=[N:56]2)=[CH:51][C:50]=1[F:71])#[N:48]
Reactant: N#Cc1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1F
Reactant: Clc1ncc(C2CC2)cn1
Agent: CCCc1cnc(Cl)nc1
Agent: Cl
Agent: N#Cc1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCNCC1
Product: CCCc1cnc(N2CCC(Oc3cc(=O)n(-c4ccc(C#N)c(F)c4)nc3C#N)CC2)nc1
Yield: 56 %

Procedure:
Example 38 was prepared in 56% yield according to procedures described in Example 21 substituting 2-chloro-5-cyclopropylpyrimidine and 1-(3,4-dichlorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl for 2-chloro-5-propylpyrimidine and 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt. 1H NMR (400 MHz, CDCl3) δ ppm 0.93 (t, J=7.25 Hz, 3H) 1.48-1.67 (m, 2H) 1.82-2.01 (m, 2H) 2.01-2.17 (m, 2H) 2.41 (t, J=7.69 Hz, 2H) 3.60-3.91 (m, 2H) 3.98-4.27 (m, 2H) 4.48-4.87 (m, 1H) 6.32 (s, 1H) 7.52-7.70 (m, 2H) 7.70-7.81 (m, 1H) 8.17 (s, 2H). MS (ESI) 460 (M+H).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH2:8][CH:7](O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1COc2c(F)cccc21
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Fc1cccc2ccoc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 235.1 %

Procedure:
To a solution of 7-fluoro-2,3-dihydrobenzofuran-3-ol (4.6 g, 29 8 mmol) in pyridine (93 mL) at 0° C. was added SOCl2 (21.7 mL, 298 mmol) dropwise. Upon completion of addition, the mixture was stirred at 0° C. for 1.5 h. At the conclusion of this period, the reaction mixture was carefully quenched with aqueous NaHCO3 (saturated, 100 mL) to reach a pH=9. Once at the prescribed pH, the reaction mixture was extracted with CH2Cl2 (4×15 mL). The combined organic layers were washed with aqueous NaHCO3 (5%, 40 mL), water (40 mL), and then concentrated to yield the crude product. The crude product was dissolved in CH2Cl2 (50 mL), washed with aqueous HCl (1 N, 5×10 mL), and then water (40 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated to afford Compound 1C as a brown oil (2.56 g). 1H NMR (500 MHz, CDCl3) δ ppm 7.67 (d, J=2.2 Hz, 1 H), 7.33-7.40 (m, 1 H), 7.17 (td, J=8.0, 4.4 Hz, 1 H), 7.04 (dd, J=10.7, 8.0 Hz, 1 H), 6.79-6.85 (m, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]>CN(C)C=O.C(NCC)C.[Cu]I.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>[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[C:26][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 65.2 %

Procedure:
A mixture of 382 mg (1 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 91 mg (1.1 mmole) 3,3-dimethyl-1-butyne, 38 mg copper(I)-iodide and 35 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 1 hour in 5 ml dimethylformamide and 5 ml diethylamine. The solvents are removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Recrystallisation of the residue from ethanol yields 250 mg (65%) pure 4-[2-(3,3-dimethyl-but-1-ynyl)-6-pyrrolidine-1-yl-pyridine-4-sulfonyl]-phenylamine als a light brown solid mp.: 242-244° C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[C:11]([Br:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17](I)[CH:16]=2)=[C:9]([Br:23])[CH:8]=1)(C)[C:3]([O-:5])=[O:4].[C:24]1([CH3:32])[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[CH:31])[CH:25]=1.[CH2:33](N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.ClCCl>[Br:23][C:9]1[CH:8]=[C:7]([CH:2]([CH3:1])[C:3]([O:5][CH3:33])=[O:4])[CH:12]=[C:11]([Br:13])[C:10]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]2[O:21][C:30]([C:26]3[CH:25]=[C:24]([CH3:32])[CH:29]=[CH:28][CH:27]=3)=[CH:31][C:17]=2[CH:16]=1
Reactant: CC(C)(C(=O)[O-])c1cc(Br)c(Oc2ccc(O)c(I)c2)c(Br)c1
Reactant: C#Cc1cccc(C)c1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Product: COC(=O)C(C)c1cc(Br)c(Oc2ccc3oc(-c4cccc(C)c4)cc3c2)c(Br)c1
Reaction time: 2 h

Procedure:
Methyl[3,5-dibromo-4-(4-hydroxy-3-iodophenoxy)phenyl]propionate (17 mg), 3-tolylacetylene (20 mg) and bis(triphenylphosphine)palladium(II) chloride (2.0 mg), copper(I) iodide (1.0 mg) and triethylamine (1 mL) was stirred at reflux. After 2 hours, the reaction mixture was cooled down, dichloromethane was added and washed once with a saturated solution of aqueous ammonium chloride. The organic phase concentrated and the residue purified on column (silica gel, n-heptane/ethyl acetate 8:2), to give 19 mg of methyl {3,5-dibromo-4-[2-(3-tolyl)-5-benzofuranyloxy]phenyl}propionate as a pale yellow solid mass. 1H-NMR (270 MHz, Acetone-d6): δ 7.68 (s, 2H), 7.53 (dd, 1H), 7.36 (t, 2H), 7.21 (d, 2H), 6.89 (m, 2H), 3.64 (s, 3H), 2.98 (t, 2H), 2.74 (t, 2H), 2.40 (s, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19]2[C:20](F)=[N:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:27][CH:26]=3)[CH:24]=2)[C:13]=1[CH:39]=[CH2:40]>C1COCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[Cl:11][C:12]1[N:17]=[CH:16][C:15]2[NH:18][C:20]3[N:21]=[CH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:27][CH:26]=4)=[CH:24][C:19]=3[C:14]=2[C:13]=1[CH:39]=[CH2:40]
Reactant: C=Cc1c(Cl)ncc(N)c1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1c(Cl)ncc2[nH]c3ncc(-c4ccc(CN5CCCCC5)cc4)cc3c12
Yield: 24.8 %

Procedure:
Sodium bis(trimethylsilyl)amide (1.3 mL, 1.3 mmol) was added to a solution of 6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-5′-vinyl-[3,4′]bipyridinyl-3′-ylamine (53 mg, 0.13 mmol) in anhydrous THF (1 mL) and the resultant solution stirred at ambient temperature for 20 min. The reaction mixture was diluted with brine (5 mL) and ethyl acetate (5 mL). The resultant precipitate was collected by filtration to afford the title compound as a beige powder (13 mg, 26%). 1H NMR (CDCl3, 400 MHz): 8.85 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.61 (s, 1H), 7.58-7.55 (m, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.22-7.14 (m, 1H), 6.03-6.01 (m, 1H), 5.99-5.97 (m, 1H), 3.56 (s, 2H), 2.47-2.37 (m, 4H), 1.64-1.59 (m, 4H), 1.52-1.44 (m, 2H). LCMS (Method A): RT=6.81 min, M+H+=403/405.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:9]1[C:10]([C:16]2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C=O)C.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:9]1[C:10]([C:16]2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:11][C:12]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCNCC2)nc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 2-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]indole-1-carboxylate (100 mg, 0.1696 mmol) and piperazine (146.1 mg, 1.696 mmol) in DMF (2 mL) was heated at 100° C. for 30 minutes and then allowed to cool to ambient temperature. The reaction was diluted with EtOAc/water and the organic layer washed further with water (2×), dried (MgSO4) and concentrated in vacuo. The material was used crude in the next step (quantitative yield assumed). MS (ES+) 595.09
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:12][CH3:13])=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1.[I-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[NH2:26]>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[NH:26][CH2:3][C:4]1[C:5]([NH:12][CH3:13])=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1
Reactant: CNc1nc(SC)ncc1CCl
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CNc1nc(SC)ncc1CNc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Yield: 97 %

Procedure:
15.85 g (5-Chloromethyl-2-methylsulfanyl-pyrimidin-4-yl)-methyl-amine hydrochloride, 1.979 g sodium iodide, and 34.49 mL N—N-diisopropylethylamine were solved in 150 ml acetonitrile and cooled to 0° C. 17.085 g 2-Chloro-5-nitrophenylamine dissolved in 150 ml acetonitrile were added slowly under stirring. The reaction mixture was stirred at room temperature for 48 hrs, then the solvent was evaporated. The residue was solved in a mixture of water/acetic acid ethyl ester (1:1), stirred and the crystalline product was sucked off and dried for 48 h under vacuum at 40° C. The two phases of the mother liquor were separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate, the solvent was evaporated and the residue was rubbed with diethyl ether. Both residues were combined and gave of the title product in 97% yield.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:9]([O:18][CH3:19])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])(OCC)=O.CCOCC>O.C(#N)C>[C:32]1(=[O:41])[N:1]([CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:9]([O:18][CH3:19])[CH:8]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCCCOc1ccc(C(N)CC(=O)O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: CCCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a stirred solution of 3-amino-3-(4'-butoxy-3'-methoxyphenyl)propionic acid (1.31 g, 4.98 mmol) and sodium carbonate (0.554 g, 5.23 mmol) in a mixture of 100 mL of water and 100 mL of acetonitrile (mixture was warmed gently to dissolve solid, small amount of brown solid did not dissolve removed by filtration) was added N-carbethoxyphthalimide (1.09 g, 4.98 mmol). The mixture was stirred for 1 hour, then partially concentrated in vacuo to remove the acetonitrile. The pH was adjusted to 0-1 with 4N Hydrochloric acid. An oil formed, 3 mL of ether was added and the mixture stirred overnight. The oil did not solidify and was extracted in methylene chloride. The organic layer was dried (sodium sulfate) and concentrated to a yellow oil which was purified by flash chromatography (silica gel, 5/95 methanol/methylene chloride) to afford 1.02 g of 3-phthalimido-3-(4'-butoxy-3'-methoxyphenyl)propionic acid containing an unidentified impurity as a yellow oil which slowly crystallized: 1H NMR (DMSO-d6) δ 7.95-7.8 (m, 4 H, Ar), 7.03 (s, 1 H), 6.9 (m, 2 H), 5.61 (dd, 1 H, J=9, 6.7 Hz), 3.91 (t, 2 H, J=6.4 Hz), 3.74 (s, 3 H), 3.47 (dd, 1 H, J=16.5, 6.7 Hz), 3.27 (dd, 1 H, J=16.5, 6.7 Hz), 1.75-1.55 (m, 2 H) 1.5-1.3 (m, 2 H), 0.91 (t, 3 H, J=7.3 Hz); 13C NMR (DMSO-d6) δ 171.8, 167.7, 148.8, 147.8, 134.6, 131.3, 131.1, 123.2, 119.3, 112.9, 111.4, 67.8, 55.5, 50.1, 30.8, 18.7, 13.6.
Reaction SMILES: [CH2:1]([N:8]([CH3:29])[CH2:9][CH2:10][CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([CH:27]=O)[CH:24]=[CH:23][N:22]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH2:1]([N:8]([CH3:29])[CH2:9][CH2:10][CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([CH2:27][NH:33][CH:30]2[CH2:32][CH2:31]2)[CH:24]=[CH:23][N:22]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCN(Cc1cc(C=O)ccn1)C(=O)OC(C)(C)C)Cc1ccccc1
Reactant: NC1CC1
Product: CN(CCCN(Cc1cc(CNC2CC2)ccn1)C(=O)OC(C)(C)C)Cc1ccccc1

Procedure:
By General Procedure A from tert-butyl N-{3-[benzyl(methyl)amino]propyl}-N-[(4-formylpyridin-2-yl)methyl]carbamate and cyclopropanamine. Purification by column chromatography using DCM:MeOH:NH4OH (8:2:1) gave the title compound. 1H NMR (300 MHz, CDCl3), (rotamers) δ ppm: 8.4 (d, 1H), 7.4-7.2 (m, 7H), 4.5 (s, 2H), 3.9 (s, 2H), 3.7-3.2 (m, 4H), 2.6-1.7 (m, 8H), 1.4 (d, 9H), 0.6-01.3 (m, 4H).
Reaction SMILES: C1[C:6]([S:7]SC2C=CC([N+]([O-])=O)=C(C(O)=O)C=2)=CC(C(O)=O)=C([N+]([O-])=O)C=1.[CH2:27]([N:38](CC(O)=O)CC(O)=O)[CH2:28][N:29](CC(O)=O)[CH2:30][C:31]([OH:33])=[O:32].P([O-])([O-])([O-])=[O:48].[K+].[K+].[K+]>>[CH2:6]([SH:7])[C@H:27]([NH2:38])[C:28]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:48]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: O=P([O-])([O-])[O-]
Reactant: O=C(O)c1cc(SSc2ccc([N+](=O)[O-])c(C(=O)O)c2)ccc1[N+](=O)[O-]
Agent: [K+]
Product: N[C@@H](CS)C(=O)NCC(=O)O

Procedure:
DTNB (5,5′-Dithio-bis-(2-nitrobenzoic acid; MM=396.36 g/mol) was prepared at 3.9 mg/ml (equivalent to 10 mM) in potassium phosphate buffer 50 mM, pH=7.5+0.1 mM EDTA. The reagent was used at 0.5 mM final concentration.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=2[N:3]=1.Cl.COC(=O)[C@H](C[SH:35])N.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(O)(=O)C>[SH:35][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=2[N:3]=1
Reactant: COC(=O)[C@@H](N)CS
Reactant: CC(C)=CCn1c(Br)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(S)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
50 mg of 8-bromo-3-methyl-7-(3-methylbut-2-enyl)-1-(2-oxo-2-phenylethyl) -3,7-dihydropurine-2,6-dione were dissolved in 1 ml of dimethylformamide and, after addition of 24 mg of L-cysteine methyl ester hydrochloride and 37 mg of potassium carbonate, the mixture was heated with stirring at 90° C. for 1 hour. After cooling to room temperature, 10 ml of water were added, and the mixture was made weakly acidic with glacial acetic acid. A precipitate separated out on stirring and was filtered off and dried in a vacuum.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][O:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCC1CCCO1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 2-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:13][O:14][C:15](=[O:19])[CH2:16][NH:17][CH3:18].C(N(CC)CC)C.O>ClCCCl>[CH3:13][O:14][C:15](=[O:19])[CH2:16][N:17]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)CN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
In 1,2-dichloroethane (50 ml) were suspended p-nitrobenzaldehyde (5 g), sarcosine methyl ester hydrochloride (4.6 g) and triethylamine (4.6 ml), and to the mixture was added, under ice-cooling, triacetoxy sodium boron hydride (9.8 g). Under nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours. To the mixture was added water, and the mixture was concentrated, neutralized with sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give N-(4-nitrobenzyl)sarcosine methyl ester (6.3 g) as colorless oil.