Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]=[C:2]1[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]1[C:20](=[O:21])[CH2:19][N:18]=[C:17]([N:22]3[CH:26]=[C:25]([CH2:27][CH3:28])[N:24]=[CH:23]3)[CH:16]=[C:11]12>C1COCC1.[Ni]>[CH2:27]([C:25]1[N:24]=[CH:23][N:22]([C:17]2[CH:16]=[C:11]3[C:12]4[C:7]([CH2:8][CH2:9][N:10]3[C:20](=[O:21])[CH2:19][N:18]=2)=[C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH:15]=[CH:14][CH:13]=4)[CH:26]=1)[CH3:28]
Reactant: CCc1cn(C2=NCC(=O)N3CCc4c(C5=CCCO5)cccc4C3=C2)cn1
Agent: [Ni]
Solvent: C1CCOC1
Product: CCc1cn(C2=NCC(=O)N3CCc4c(cccc4C4CCCO4)C3=C2)cn1
Temperature: 25 °C
Reaction time: 36 h
Yield: 25 %

Procedure:
Example 111. A flask was charged with 9-(4,5-dihydrofuran-2-yl)-2-(4-ethyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (250 mg, 0.67 mmol) in 20 mL THF and Raney-Nickel (100 mg, 0.67 mmol) was added. The flask was evacuated in vacuo and then filled with H2. The mixture was stirred at RT for 36 h. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue obtained was purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1) and the product obtained was recrystallized from heptane to give the title compound (63 mg; racemic) as beige solid. UPLC-MS: MS 377.3 (M+H+); UPLC rt 0.83 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.13 (t, J=7.62 Hz, 3H); 1.47-1.64 (m, 1 H); 1.81-2.00 (m, 2 H); 2.24-2.40 (m, 1 H); 2.40-2.55 (m, 2 H); 2.74-3.04 (m, 2 H); 3.59-3.74 (m, 1 H); 3.81 (q, J=7.56 Hz, 1 H); 3.86-3.97 (m, 1 H); 4.03 (q, J=7.17 Hz, 1 H); 4.21 (br. s., 2 H); 5.04 (t, J=7.04 Hz, 1 H); 7.06-7.17 (m, 1 H); 7.25-7.44 (m, 2 H); 7.52 (d, J=7.43 Hz, 1 H); 7.89 (d, J=8.21 Hz, 1 H); 8.12 (s, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[CH:15][C:16](Br)=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](N1CCN2C(=O)C3C(Br)=CC=CC=3C[C@@H]2C1)[C:25]1C=CC=C[CH:26]=1.C(B(O)O)(C)=C.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[CH:15][C:16]([C:25]([CH3:26])=[CH2:24])=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Br)cccc2C[C@@H]2CN(Cc3ccccc3)CCN12
Reactant: O=C1c2ccc(Br)cc2C[C@@H]2CN(Cc3ccccc3)CCN12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(C)B(O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: C=C(C)c1ccc2c(c1)C[C@@H]1CN(Cc3ccccc3)CCN1C2=O
Temperature: 80 °C

Procedure:
A degassed mixture of (R)-2-benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one with (R)-2-benzyl-7-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (9-Br:7-Br=1:2, 100 mg, 0.27 mmol), isopropenyl boronic acid (46 mg, 0.54 mmol), tetrakis(triphenylphosphine)palladium (16 mg, 0.013 mmol) and K2CO3 (82 mg, 0.59 mmol) in DME (2 mL) and water (0.6 mL) was heated at 80° C. for 9 h to give dark brownish reaction mixture. The mixture was then cooled, quenched with 10 mL of water, extracted with ethyl acetate (3×10 mL), dried over MgSO4, and concentrated in vacuo to give the desired product as brown oil (No 7-isomeric product was observed).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:11][CH:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:1]([NH:4][CH:12]([CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH3:3]
Reactant: CC(Br)c1ccccc1
Reactant: CCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCNC(C)c1ccccc1
Yield: 95 %

Procedure:
Introduce 23 ml of propylamine into 200 ml of dimethylformamide, add 32 g of caesium carbonate and 9.25 g of α-methylbenzyl bromide. Leave for 4 hours at room temperature. Evaporate to dryness and take up with water. Extract with ethyl acetate, dry over anhydrous sodium sulphate and evaporate to dryness to obtain the expected product.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[C:21]1[N:22]2[N:28]=[C:27]([O:29][CH3:30])[C:26]([NH:31][CH2:32][CH2:33][CH3:34])=[C:23]2[S:24][CH:25]=1.Br[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.CC(C)([O-])C.[Na+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[C:21]1[N:22]2[N:28]=[C:27]([O:29][CH3:30])[C:26]([N:31]([CH2:32][CH2:33][CH3:34])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[C:23]2[S:24][CH:25]=1
Reactant: CCCNc1c(OC)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Reactant: Brc1ccccn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCN(c1ccccn1)c1c(OC)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 21.7 %

Procedure:
To a toluene (0.9 mL) solution of 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxy-N-propylpyrazolo[5,1-b][1,3]thiazole-7-amine (70 mg, 0.179 mmol) were added 2-bromopyridine (56.6 mg, 0.358 mmol), sodium tert-butoxide (25.8 mg, 0.269 mmol) and bis(tri-tert-butylphosphine)palladium (4.57 mg, 0.009 mmol), and the mixture was stirred at 100° C. for five hours. After the reaction mixture was returned to room temperature, water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure amino silica gel column chromatography (n-heptane/ethyl acetate: 10% then 50%) to obtain the title compound (18.2 mg, 0.0388 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.C(O)(=O)C.[C:9]([O:13][C:14]([N:16]1[CH:20]=[CH:19][C:18]([NH2:21])=[N:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH:20]=[CH:19][C:18]([NH:21][CH:2]([CH3:4])[CH3:1])=[N:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Nc1ccn(C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of acetone (0.1 mL, 1.4 mmol), acetic acid (0.078 mL, 1.43 mmol) and 3-amino-pyrazole-1-carboxylic acid tert-butyl ester (200 mg, 1.1 mmol) in DCM (5 mL) was stirred at RT for 1 hour. Sodium triacetoxyborohydride (467 mg, 2.2 mmol) was added and the mixture stirred overnight. The mixture was extracted with ethyl acetate, washed with water, dried and concentrated. The residue was purified by flash column to give 3-Isopropylamino-pyrazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:12][Br:13])=[CH:8][C:9]=1[O:10][CH3:11])=O.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Br:13][CH2:12][C:7]1[S:6][C:5]([CH2:3][OH:2])=[C:9]([O:10][CH3:11])[CH:8]=1
Reactant: COC(=O)c1sc(CBr)cc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1cc(CBr)sc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a solution of 5-bromomethyl-3-methoxy-thiophene-2-carboxylic acid methyl ester (1.4 g, 5.2 mmol) in anhydrous dichloromethane (50 mL) is added diisobutyl aluminum hydride (1M in hexane, 21.0 mL, 21.1 mmol) dropwise at −78° C. After the completion of the addition, the mixture is warmed to room temperature and stirred for 2 hours. The reaction mixture is quenched with water (15 mL) at −40° C. and the mixture is agitated for 30 minutes at room temperature. The reaction mixture is filtered through diatomaceous earth. The filtrate is dried over sodium sulfate and concentrated, to give the title compound as a pale yellow liquid (1.2 g, 96%). 1H NMR (400 MHz, d6 DMSO) 7.46 (s, 1H), 4.58 (s, 2H), 3.84 (s, 3H), 3.73 (s, 2H).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH2:4]([O:3][C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](=[O:15])[NH:22][CH:19]1[CH2:21][CH2:20]1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NC1CC1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NC1CC1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
A mixture of carbobenzyloxy-L-proline (994 mg, 3.99 mmol), cyclopropylamine (0.41 mL, 5.9 mmol), HOBt (807 mg, 6 mmol), EDC (1.12 g, 5.9 mmol) and TEA (1.1 mL) in DMF (11 mL) was stirred at room temperature for 48 hours. The reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was column chromatographed to give 985 mg (81%) of (S)-2-cyclopropylcarbamoyl-pyrrolidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:31]=[CH:30][N:29]=[CH:28][C:21]=5[C:22]5[N:23]([CH:25]=[N:26][N:27]=5)[N:24]=4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32](NN)(=O)C>>[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:31]=[CH:30][N:29]=[CH:28][C:21]=5[C:22]5[N:23]([C:25]([CH3:32])=[N:26][N:27]=5)[N:24]=4)=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)NN
Reactant: c1cc2c(-c3ccc(OC4CCN(C5CCCC5)CC4)cc3)nn3cnnc3c2cn1
Product: Cc1nnc2c3cnccc3c(-c3ccc(OC4CCN(C5CCCC5)CC4)cc3)nn12

Procedure:
The compound of Example 82 was obtained as a pale yellow solid in the same manner as in Example 2 and Example 79 or according to a method similar to it or according to a combination of the method with an ordinary method, but using 4-chloro-1-(4-methoxyphenyl)-pyrido[3,4-d]pyridazine obtained in Example 79 and acetohydrazide in place of formylhydrazide.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[O:29])[O:27][C:26]([CH3:31])([CH3:30])[O:25][C:24]=2[CH:32]=1.C(CC1SC=C(C2SC(NC(=O)C)=NC=2C)N=1)#N.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[C:28](=[O:29])[O:27][C:26]([CH3:30])([CH3:31])[O:25][C:24]=4[CH:32]=3)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Agent: CC(=O)Nc1nc(C)c(-c2csc(CC#N)n2)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Nc3ccc4c(c3)OC(C)(C)OC4=O)n2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 7-Amino-2,2-dimethyl-4H-1,3-benzodioxine-4-one, Amine 3 prepared as described above, (128.0 mg; 0.66 mmol; 1 eq.) and triethylamine (0.19 ml; 1.33 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by crystallization in MeOH. The resulting product is washed with MeOH and NaHCO3 (sat), affording 2′-(acetylamino)-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)-4′-methyl-4,5′-bi-1,3-thiazole-2 carboxamide as a beige solid (200 mg; 65%). 1H NMR (DMSO-d6, 300 MHz) δ 1.67 (s, 6H), 2.13 (s, 3H), 2.49 (s, 3H), 7.28 (m, 1H), 7.56 (s, 1H), 7.64 (br d, J=9 Hz, 1H), 7.75 (s, 1H), 11.65 (br s, 1H). M− (ESI): 457.08; M+ (ESI): 459.13. HPLC (method A), Rt: 3.86 min (purity: 97.7%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[CH3:32][C:29]([CH3:30])([CH3:31])[C:28](=[O:33])[CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]([C:12]2[CH:13]=[CH:14][C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=3[CH:11]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:21][C:22]=1[CH3:34]
Reactant: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of 6-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.89 g, 1.86 mmol) in MeOH (5.0 mL) and THF (5.0 mL) and is treated with NaOH (2.0 M, 10.0 mL). The resulting mixture is stirred at RT for 2 h. The mixture is concentrated, acidified with HCl (1 N) until pH-3, and extracted with EtOAc (2×50 mL). The organic layer is dried over Na2SO4, concentrated, and purified using silica gel column chromatography (50% EtOAc/Hex) to afford the title compound (840 mg, 99%).
Reaction SMILES: C(Cl)(Cl)(Cl)[Cl:2].[C:6]([CH2:8][NH:9][C:10](=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:15]([O:25][CH3:26])[CH:14]=1)#[N:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Cl:2][C:6]1[N:7]=[C:10](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:15]([O:25][CH3:26])[CH:14]=2)[NH:9][CH:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1cc(/C=C/C(=O)NCC#N)ccc1-n1cnc(C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc(/C=C/c2nc(Cl)c[nH]2)ccc1-n1cnc(C)c1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
Carbon tetrachloride (0.326 mL) was added to a solution of (E)-N-cyanomethyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (400 mg) and triphenylphosphine (888 mg) in acetonitrile (20 mL), and the reaction solution was stirred at 45° C. for 12 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate) to obtain 76 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24].[Li+].[OH-]>C1COCC1.CO.O>[F:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24]
Reactant: COC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-fluoro-5-(2-fluoro-4-iodophenylamino)-1-methyl-1H-benzo[d]imidazole-6-carboxylate (2.15 g, 4.8 mmoles) is dissolved in a mixture of THF (30 ml), MeOH (10 ml) and H2O (5 ml) and LiOH (1.16 g, 4.8 mmoles) is added. The mixture is stirred at room temperature for 2 hours. Solvents are removed under reduced pressure and 1N HCl is added. The aqueous layer is extracted with chloroform. The organic layers are combined, washed with brine, dried (Na2SO4) and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.C.O.NN>CO>[N:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccncc2)cc1
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
4-(4-nitro-phenyl)-pyridine (250 mg, 1.25 mmol) is dissolved in MeOH (20 mL). To this solution is added FeCl3.6H2O (24 mg, 0.09 mmol) and active charcoal (12 mg, 1.0 mmol). The suspension is heated to reflux. Hydrazine hydrate (1.3 mL) is added, and reflux is continued for 3 h. After the mixture is cooled to room temperature, the active charcoal is filtered off through Celite, and the MeOH is removed under reduced pressure. The residue is purified with flash chromatography to provide the 4-pyridin-4-yl-phenylamine (200 mg, 94%). 1H NMR (400 MHz, CDCl3) ∂ 8.57 (2H, d, J=8.8 Hz), 7.44-7.52 (4H, m), 6.77 (2H, d, J=7.2 Hz), 3.87 (2H, br); MS (ESI) m/z 171 (M+H)+1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(N(CC)C(C)C)(C)C.[CH3:38][C:39]([CH3:59])=[CH:40][CH2:41][CH2:42]/[C:43](/[CH3:58])=[CH:44]/[CH2:45][CH2:46]/[C:47](/[CH3:57])=[CH:48]/[CH2:49][S:50][CH2:51][C@H:52]([NH2:56])[C:53]([OH:55])=[O:54]>C(Cl)Cl.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([NH:56][C@@H:52]([CH2:51][S:50][CH2:49]/[CH:48]=[C:47](\[CH3:57])/[CH2:46][CH2:45]/[CH:44]=[C:43](\[CH3:58])/[CH2:42][CH2:41][CH:40]=[C:39]([CH3:59])[CH3:38])[C:53]([OH:55])=[O:54])=[O:10]
Reactant: O=C(O)CCc1ccco1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CCc1ccco1)C(=O)O
Reaction time: 0.17 h

Procedure:
To a solution of 3-(2-furyl) propionic acid (168 mg, 1.2 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 332 mg, 1.2 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropyl-ethyl-amine (0.52 mL, 3 mmol). After stirring for 10 min, S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added slowly. The solution was stirred at room temperature overnight and then diluted with ethyl acetate (60 mL). The solution was washed by 0.5 N HCl (10 mL×1), H2O (10 mL×1) and brine (10 mL×1). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (333 mg, 74%) to yield Compound N-96. 1H-NMR (500 MHz, CD3OD): δ 1.50 (s, 6H), 1.57 (s, 3H), 1.59 (s, 3H), 1.86-1.89 (m, 2H), 1.95-2.06 (m, 6 H), 2.51 (t, J=8.0 Hz, 2H), 2.57-2.62 (m, 1H), 2.83-2.869 (m, 3H), 3.05 (dd, J=7.5, 13.5 Hz, 1H), 3.12-3.16 (m, 1H), 4.49 (dd, J=4.5, 8.0 Hz, 1H), 4.99-5.01 (m, 2H), 5.13 (t, J=7.5 Hz, 1H). 13C-NMR (125 MHz, CD3OD): δ 16.15, 16.24, 17.80, 24.96, 25.95, 27.39, 27.79, 30.11, 33.41, 35.08, 40.79, 40.89, 53.30, 106.28, 111.19, 121.61, 125.14, 125.46, 132.12, 136.27, 140.49, 142.36, 155.72, 174.00, 174.78; ES-MS: mass calcd for Chemical Formula: C25H37NO4S 447.63. Found (M+1) m/z 448.3, (M+23) m/z 470.2.
Reaction SMILES: [Cl-].[C:2]([CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([I:16])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]1[C:17](=[O:20])[CH2:18][NH3+:19])(O)=[O:3].C(OC(NCC(N1CCC2C(=CC=CC=2I)C1CC([O-])=O)=O)=O)(C)(C)C.[Na+].Cl>O1CCOCC1>[I:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH2:9][CH2:8][N:7]1[C:17](=[O:20])[CH2:18][NH:19][C:2](=[O:3])[CH:5]=[C:6]12
Reactant: [NH3+]CC(=O)N1CCc2c(I)cccc2C1CC(=O)O
Agent: CC(C)(C)OC(=O)NCC(=O)N1CCc2c(I)cccc2C1CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1COCCO1
Product: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(1-(carboxymethyl)-5-iodo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanaminium chloride. A suspension of sodium 2-(2-(2-((tert-butoxycarbonyl)amino)acetyl)-5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (49.8 g, 100 mmol) in dry dioxane (1 L) was treated with an aqueous solution of HCl (4M, 280 ml, 1.12 mol) and the mixture was stirred at RT for 18 h. The reaction mixture was then concentrated in vacuo to give the title compound (46.1 g) as a beige powder that was used as it is in the next step. UPLC-MS: MS 375.1 (M+H+); UPLC rt 0.60 min.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=[O:2].O1CCOCC1.CO.[BH4-].[Na+]>O>[OH:2][CH2:1][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2c(CO)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 5f (315 mg, 0.772 mmol) was placed in a 40 mL vial equipped with a stir bar and then dioxane (10 mL) and MeOH (10 mL) were added. NaBH4 (51.0 mg, 1.35 mmol) was added and then the reaction was stirred at rt for 18 h. The reaction was diluted with water (20 mL) and the mixture was extracted with DCM (3×25 mL). The organic extracts were combined, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to afford compound 34a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.09-8.17 (m, 2H), 8.06 (d, J=5.6 Hz, 1H), 7.75-7.86 (m, 2H), 6.15 (d, J=5.6 Hz, 1H), 4.86 (d, J=5.6 Hz, 2H), 3.87-4.05 (m, 8H), 2.52 (t, J=5.6 Hz, 1H), 1.61 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H26N4O4: 411.2 (M+H). Found: 411.4.
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:25]=[C:24]([CH:26]=O)[CH:23]=[C:22]([O:28][CH3:29])[C:18]=1[NH:19][CH:20]=[O:21]>CS(C)=O>[NH:4]([CH:11]=[C:12]([C:13]#[N:14])[CH2:26][C:24]1[CH:23]=[C:22]([O:28][CH3:29])[C:18]([NH:19][CH:20]=[O:21])=[C:17]([O:16][CH3:15])[CH:25]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1cc(C=O)cc(OC)c1NC=O
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(CC(C#N)=CNc2ccccc2)cc(OC)c1NC=O

Procedure:
A mixture of 2.7 g. of sodium methylate, 3.65 g. of β-anilino-propionitrile and 4.2 g. of 2',6'-dimethoxy-4'-formyl-formanilide in 30 ml. of absolute dimethylsulfoxide was stirred at 50° C. for 30 minutes. The solution was poured into 500 ml. of water and the resulting emulsion extracted with two 500 ml. portions of ethyl acetate. The ethyl acetate extract was washed with two 300 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. The residue was recrystallized from ethyl acetate and there was obtained 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxy-formanilide having a melting point of 186°-187° C.