Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][C@@H:7]([NH:9]C(=O)OCC1C=CC=CC=1)[CH3:8].O=[C:26]([CH3:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[NH2:24][C:23]1[C:3]2[C:2](=[CH:22][CH:21]=[CH:20][C:4]=2[O:5][CH2:6][C@@H:7]([NH2:9])[CH3:8])[N:1]=[C:26]([CH3:33])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: C[C@@H](COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N

Procedure:
Prepared as in Example 2a from (S)-benzyl (1-(3-amino-2-cyanophenoxy)propan-2-yl)-carbamate (Example 26c) and ethyl 3-oxobutanoate as brown solid. MS 304 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:12][CH:10]([C:4]1[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([NH2:1])[N:3]=1)[CH3:11]
Reactant: CSc1nc(N)nc(C(C)O)n1
Reactant: Oc1ccccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1nc(N)nc(C(C)Oc2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
To a solution of 1-(4-amino-6-(methylthio)-1,3,5-triazin-2-yl)ethanol (203 mg) in dry tetrahydrofuran (8 mL) was added 2-chlorophenol (0.122 mL) and triphenylphosphine (314 mg) followed by diisopropyl azodicarboxylate ((0.233 mL) dropwise. The solution was stirred at room temperature for 80 min then was concentrated in vacuo, dissolved in ethyl acetate (40 mL) and washed with 1N sodium hydroxide solution (2×40 mL), dried over sodium sulfate and concentrated to give a yellow oil. Purification by SCX chromatography eluting with a 1:1 mixture of dichloromethane-methanol then 2N ammonia in 1:1 mixture of dichloromethane-methanol followed by flash column chromatography, with 1% acetonirile in dichloromethane to give the title compound (207 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]CC4C=CC=CC=4)[CH:15]=3)[CH:10]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][NH:38]3)=[CH:30][CH:29]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[CH:10]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][NH:38]3)=[CH:30][CH:29]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(OCCC3CCCCN3)cc2)cc1Cl
Solvent: CCOC(C)=O
Product: Oc1ccc2c(c1)CCN(c1ccc(Cl)c(Cl)c1)C2Cc1ccc(OCCC2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 3.1 %

Procedure:
A solution of 2-(3,4-dichlorophenyl)-6-(phenylmethoxy)-1-{4-[(2-piperidyl)ethoxy]benzyl}-1,2,3,4-tetrahydroisoquinoline (0.380 g, 0.63 mmol) was placed under a nitrogen atmosphere and dissolved in ethyl acetate (5 ml). The flask was evacuated and flushed with nitrogen. To the flask was added palladium (10% wt. on activated carbon, 0.190 g). The flask was flushed and evacuated with nitrogen followed by hydrogen. The reaction was allowed to stir under the hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered through celite and concentrated. The product was purified by preparative HLPC (C-18 column, 10-100% acetonitrile/water with 0.1% trifluoroacetic acid) to provide the title compound (0.010 g, 3% yield). 1H NMR (CDCl3) 6.7-7.2 (m, 10H), 4.7 (t, 1H), 4.2-4.4 (m, 2H), 3.6-4.0 (m, 4H), 3.3-3.6 (m, 3H), 3.0-3.1 (m, 1H), 2.7-2.9 (m, 3H), 2.6-2.7 (m, 1H), 1.8-2.1 (m, 4H), 1.4 (m, 2H); ES-MS (m/z) 511 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[CH2:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH2:30][CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:26][CH2:27][N:28]([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=2)=[O:24])[CH2:29]1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2ccccc2CC1

Procedure:
100.0 mg (0.29 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 50.0 mg (0.34 mmol) 2,3,4,5-tetrahydro-1H-3-benzazepine, 100 μL (0.71 mmol) triethylamine and 100.0 mg (0.31 mmol) TBTU in 1.5 mL DMF were stirred overnight at RT. The reaction mixture was filtered through a syringe filter and the solution was purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][F:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCCF)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 4-hydroxybenzoate (4.03 g), 1-bromo-2-fluoroethane (5.05 g) and potassium carbonate (10.98 g) in N,N-dimethylformamide (68 ml) was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, and thereto was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and brine, and then dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give methyl 4-(2-fluoroethyloxy)benzoate, which was used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: CN1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Br)c(Cl)cc21
Solvent: CS(C)=O
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Br)c(N3CCN(C)CC3)cc21
Yield: 33 %

Procedure:
3.3 g of 6-bromo-7-chloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.01 mol) and 4.5 cm3 of 1-methylpiperazine (0.04 mol) in solution in 30 cm3 of dimethylsulphoxide, were heated at 110° C. for 4 hours. After cooling, the solution was diluted with 250 cm3 of water. The precipitate formed was filtered off, washed with water and recrystallised from 50 cm3 of methyl cellosolve. 1.3 g of 6-bromo-1-ethyl-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 209C (decomposition), were obtained.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[C:10]([C:12]#[N:13])[CH:11]=1)(=[O:5])[CH3:4]>CCOCC>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH:9]=[C:10]([C:12]#[N:13])[CH:11]=1)=[O:5]
Reactant: CC(=O)c1cc(C#N)cc(NS(C)(=O)=O)c1
Reactant: BrBr
Solvent: CCOCC
Product: CS(=O)(=O)Nc1cc(C#N)cc(C(=O)CBr)c1
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Al(CH3)3 (20 mmol) was added dropwise to the ice-water cooled solution of DMEDA (4.4 mmol) in dry toluene (60 mL) under nitrogen. After addition, it was continued to stir for 2 hours at room temperature. Then, methyl-3-cyano-5-(methylsulfonamido)benzoate (4 mmol) was added, and the reaction mixture was heated to reflux overnight. After cooling, it was poured into diluted hydrochloric acid, the mixture was extracted with EtOAc, the combined organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated to afford N-(3-acetyl-5-cyanophenyl)methanesulfonamide with a yield of 35%. Br2 (1.2 mmol) was added dropwise to the solution of N-(3-acetyl-5-cyanophenyl)methanesulfonamide (1 mmol) in Et2O (50 mL). After addition, it was continued to stir for 1.5 hours. Then the reaction mixture was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated to afford N-(3-(2-bromoacetyl)-5-cyanophenyl)methanesulfonamide with a yield of 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:13][CH2:14][CH2:15][N:16]([C:18](=[O:65])[CH2:19][O:20][C@@H:21]2[C:29]3([CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C@:37]4([C:58]5[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=5)[O:41][CH2:40][N:39]([C:42](=[O:57])[C:43]5[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=5)[CH2:38]4)[CH2:31][CH2:30]3)[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)[CH3:17])[CH3:12])=[O:10])=[CH:4][CH:3]=1.[C:66]1([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[NH:72][C:73](=[O:93])[O:74][CH:75]1[CH2:80][CH2:79][N:78]([CH2:81][CH2:82][N:83]([CH3:92])[C:84](=[O:91])[CH2:85][CH2:86][CH2:87][CH2:88][CH:89]=O)[CH2:77][CH2:76]1>>[C:66]1([C:94]2[CH:95]=[CH:96][CH:97]=[CH:98][CH:99]=2)[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[NH:72][C:73](=[O:93])[O:74][CH:75]1[CH2:80][CH2:79][N:78]([CH2:81][CH2:82][N:83]([C:84](=[O:91])[CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:13][CH2:14][CH2:15][N:16]([C:18](=[O:65])[CH2:19][O:20][C@@H:21]3[C:29]4([CH2:30][CH2:31][N:32]([CH2:35][CH2:36][C@:37]5([C:58]6[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=6)[O:41][CH2:40][N:39]([C:42](=[O:57])[C:43]6[CH:44]=[C:45]([C:53]([F:54])([F:56])[F:55])[CH:46]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:48]=6)[CH2:38]5)[CH2:33][CH2:34]4)[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[CH3:17])[CH3:12])=[O:10])=[CH:4][CH:3]=2)[CH3:92])[CH2:77][CH2:76]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Reactant: CN(CCCN(C)C(=O)Cc1ccc(N)cc1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(CC(=O)N(C)CCCN(C)C(=O)CO[C@H]2Cc3ccccc3C23CCN(CC[C@@]2(c4ccc(F)cc4)CN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CO2)CC3)cc1
Yield: 31.9 %

Procedure:
The compound (194 mg, 0.219 mmol) obtained in Example 57b and the compound (102 mg, 0.219 mmol) obtained in Example 4g were used to give the title compound (95 mg; yield, 32%) as a white solid according to the method described in Example 41b.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[CH3:2].CN(CCN(CCN(C)C)C)C.C([Li])CCC.CN([CH:30]=[O:31])C>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([CH:8]=1)[CH:30]=[O:31])[CH3:2]
Reactant: CCc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(F)c(C=O)c1
Temperature: -60 °C
Reaction time: 0.67 h
Yield: 94.6 %

Procedure:
To a solution of 1-ethyl-4-fluorobenzene (10 g, 80.6 mmol) and PMDTA (17 mL) in THF (60 mL) cooled to −78° C. was added 1.6 M n-butyl lithium (56 mL, 89 mmol) dropwise and the mixture stirred for 40 min at −60° C. Mixture cooled to −78° C. and added DMF (16 mL, 202 mmol) before allowing the mixture to warm to 23° C. Quenched with aqueous NH4Cl and extracted with EtOAc (3×50 mL). Organic layer was washed with H2O and brine before concentrating to afford 11.6 g of Intermediate 311.2. 1H-NMR (CDCl3)=1.18 (t, 3 H), δ 2.58 (q, 2 H), δ 7.04 (t, 1 H), δ 7.35 (m, 1 H), δ 7.62 (m, 1 H), δ 10.31 (s, 1 H).
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH2:27])=[O:7])[CH:2]([CH3:4])[CH3:3].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][C:41](=O)[CH3:42])[CH:33]=1.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([N:5]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[CH2:25][CH2:26][NH:27][CH:41]([CH3:42])[CH2:40][CH2:39][CH2:38][C:34]1[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCN)c1
Reactant: CC(=O)CCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCNC(C)CCCc2cccnc2)c1
Yield: 48.5 %

Procedure:
To a solution of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid diisobutylamide (142 mg in dry methanol) was added 19 mg 5-pyridin-3-yl-pentan-2-one and the pH adjusted to 6 by the addition of trifluoroacetic acid. To this, approximately 10 mg of 3 Å molecular sieves were added followed by 27 mg of sodium cyanoborohydride. The pH was adjusted occasionally with trifluoroacetic acid over 36 hours to maintain pH of 6. The reaction was then quencehed by the addition of aqueous potassium carbonate and the mixture extracted with ethyl acetate. The organic portion was washed sequentially with aqueous potassium carbonate and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:8:1) gave the title compound (32 mg) [m/e =567 (M+H)] plus unreacted amine (115 mg).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][CH:30]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH:34][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:15]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=3)[CH:8]=2)=[N:31][CH:30]=1)[CH3:24]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: CC(C)COc1cc(Oc2ccc(F)cc2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(OCC(C)C)cc(Oc3ccc(F)cc3)c2)s1

Procedure:
The title compound was prepared from 3-(4-fluoro-phenoxy)-5-isobutoxy-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1Br
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: COCCOC
Product: Cc1cccnc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromo-3-picoline (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (430 mg, 83%) as a light yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH:8][C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:1][C:2]1[N:3]([N:8]([CH3:23])[C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:13][CH:14]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1Nc1ccc(N2CCOCC2)nn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1N(C)c1ccc(N2CCOCC2)nn1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To 1.36 g (5 m moles) of N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-morpholino-3-pyridazineamine in 13.6 ml of dimethylformamide, 0.26 g (5.5 m moles) of 55% sodium hydride are added. The mixture is stirred for 30 minutes at room temperature and for additional 30 minutes at 55° C. Then, a solution of 0.78 g (5.5 m moles) of methyl iodide in 2 ml of dimethylformamide is gradually added at 10° C. When the addition is completed the mixture is heated at 50° C. for 45 minutes. The dimethylformamide is evaporated off in vacuo and the residue is dissolved in ethyl acetate. The organic layer is washed with water and then evaporated to dryness to give a solid which is crystallized from hexane. Yield 0.7 g (54%) of the product of the title which melts at 119°-122° C.
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=2)[N:9]=[CH:8]1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1OB(O)O>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:7]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=2)[N:9]=[CH:8]1
Reactant: OB(O)Oc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]cn2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccccc3F)cn2)CC1
Reaction time: 72 h

Procedure:
Copper acetate (35 mg) and pyridine (0.02 ml) were added to a solution of 2 mg of the compound prepared in the above 3), i.e. tert-butyl 4-(1H-imidazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate and 35 mg of 2-fluorophenylboric acid in dichloromethane and the solution was stirred for three days. The solvent was evaporated in vacuo and the residue was separated and purified by a thin-layer chromatography (ethyl acetate/hexane=1/2) to give 2.48 mg of the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].[CH:3]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:8][C@H:9]([NH:13][C:14]([CH2:16][CH2:17][NH2:18])=[O:15])[C:10]([OH:12])=[O:11].O.O.C([O-])(=O)C.[Zn+2:25].C([O-])(=O)C>CO>[CH:3]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:8][C@H:9]([NH:13][C:14]([CH2:16][CH2:17][NH2:18])=[O:15])[C:10]([OH:12])=[O:11].[Zn:25]
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [Zn]
Reaction time: 2 h

Procedure:
Sodium hydroxide (3.51 g) was dissolved in methanol (100 ml), and L-carnosine (9.96 g) was added to the solution to prepare a uniform solution. A solution with zinc acetate dihydrate (9.67 g) dissolved in methanol (145 ml) was added dropwise over 30 minutes to the uniform solution. As a result, white precipitate was gradually formed. After completion of the addition, the mixture was stirred for 2 hours, left to stand overnight and then filtered. The resultant filter cake was then washed with water (140 ml) and air-dried at 80° C. for 5 hours to obtain a crystalline L-carnosine zinc salt (12.4 g) as white powdery crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[C:11]=2[F:20])O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>[OH-].[K+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[C:11]=2[F:20])[CH:7]=1
Reactant: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)c(F)c1F
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [K+]
Solvent: CCOCC
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)c(F)c1F
Yield: 71.7 %

Procedure:
(5-bromo-2-chloro-phenyl)-(4-ethoxy-2,3-difluoro-phenyl)methanol 3d (8.0 g, 21.2 mmol) was dissolved in 150 mL of mixed solution (acetonitrile and dichloromethane, v:v=2:1), followed by addition of triethylsilane (10.1 mL, 63.6 mmol) and boron trifluoride etherate (5.3 mL, 42.4 mmol). The reaction mixture was stirred for 3 hours, before 100 mL 2 M potassium hydroxide were added. The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system C to obtain the title compound 1-[(5-bromo-2-chloro-phenyl)methyl]-4-ethoxy-2,3-difluoro-benzene 3e (5.5 g, white solid), yield: 72.4%. MS m/z (ESI): 360.5 [M+1]. 1H NMR (400 MHz, CDCl3): δ 7.36-7.27 (m, 3H), 6.81-6.76 (dd, 1H), 6.72-6.68 (dd, 1H), 4.17-4.13 (q, 2H), 4.10 (s, 2H), 1.50-1.47 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH2:17][CH3:18])[CH:3]=1>[Pd].C(O)C>[NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH2:17][CH3:18])[CH:3]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)c(N)cc1OCC

Procedure:
Prepared analogously to example 1b from the product obtained from (599b) by hydrogenation with palladium on charcoal in ethanol.
Reaction SMILES: Br[CH2:2][C:3]([O:5]CC)=[O:4].[OH-].[Na+].[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[OH:21])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:20][O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:10]([CH3:12])[CH3:11])[C:14]=1[O:21][CH2:2][C:3]([OH:5])=[O:4]
Reactant: COc1cccc(C(C)C)c1O
Reactant: CCOC(=O)CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(C(C)C)c1OCC(=O)O
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of 11.1 ml of ethyl bromoacetate in 10 ml of toluene was added dropwise at room temperature over about 15 minutes into a mixture of 20 g of NaOH, 30 ml of H2O, 1.1 g of triethylbenzylammonium chloride, 8.4 g of 2-isopropyl-6-methoxyphenol (prepared according to Johnson et al., Tetrahedron. 38, 1397-1404 (1982)) and 40 ml of toluene. The mixture was stirred vigorously at the same temperature for 2 h and thereafter for 2 h at 60-65° C. and for 6.5 h under reflux. During this last step a solution of 6 ml of ethyl bromoacetate in 10 ml of toluene was added. In the end the mixture was diluted with 250 ml of H2O. The aqueous phase was separated off and treated with concentrated HCl; the emulsified precipitate was extracted with Et2O (3×50 ml) and the organic phase was washed with water. Another extraction was performed with 40 ml of 20% Na2CO3 and the slightly alkaline solution was treated with concentrated HCl and extracted with Et2O (3×40 ml). The extracts were pooled and the solvent was evaporated off, giving 8 g (72%) of the desired compound; b.p. 190° C./0.7 mmHg.