Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].[O:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:1]([N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[OH:20])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-allyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (1000 mg, 4.42 mmol) in DMF (10 mL) was portionwise added sodium hydride (526 mg, 13.26 mmol). After stirring at RT for 5 min., 4-(oxiran-2-yl)pyridine (669 mg, 5.31 mmol) was added dropwise into the reaction mixture, which was stirred at RT for 16 h. Ice water was added into the reaction mixture and the solid mass obtained was filtered, washed with water (2×10 mL), hexane (2×50 mL) and ether to yield 2-(2-allyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.6 (d, 2H), 7.24 (s, 1H), 7.2 (d, 2H), 7.0 (d, 2H), 5.98 (m, 1H), 5.2 (dd, 2H), 5.0 (m, 1H), 4.1 (m, 2H), 3.6 (dd, 2H), 3.22 (d, 2H), 2.7-2.9 (m, 3H), 2.6 (m, 1H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers II-63a-b.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4](=[O:12])[C:3]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:21][CH:20]=1
Reactant: COC(=O)c1c(Cl)c2ccccc2[nH]c1=O
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1c(NCc2ccc(OC)cc2)c2ccccc2[nH]c1=O
Temperature: 90 °C

Procedure:
Methyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 69) (0.928 g, 3.91 mmol) was dissolved in DMF (6 mL), and 4-methoxybenzylamine (1.14 mL, 8.78 mmol) was added. The reaction was heated at 90° C. for 30 minutes, then cooled to room temperature and poured into a stirred mixture of 50 mL hexanes and 100 mL ice water. The resultant precipitate was collected by filtration and further chromatographed on silica gel (0% to 20% MeOH in dichloromethane) to give methyl 4-(4-methoxybenzylamino)-2-oxo-1,2-dihydroquinoline-3-carboxylate as an off white solid (0.841 g, 64%). MS 339 (MH+).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C[Si]([N:19]=[N+:20]=[N-:21])(C)C>>[CH2:12]([C:13]1[N:19]=[N:20][NH:21][CH:14]=1)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#CCCCCCCCCCCCC
Product: CCCCCCCCCCCCc1c[nH]nn1
Reaction time: 14 h
Yield: 49.8 %

Procedure:
A mixture of 1-tetradecyne (6.6 g, 34 mmol) and trimethylsilyl azide (4.1 g, 35 mmol) was autoclaved at 135° C. for 14 hours and then at 150° C. for 14 hours. The resulting mixture was rinsed with ether and the ether solution was washed with water, dried over MgSO4, filtered, and concentrated to give a brown oil. Triturated with cold hexanes to give the title compound as a tan solid (4.02 g, 50%); mp 64°-67° C.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:24]=[CH:23][C:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH:20](O)[CH3:21])[C:18]=3[C:10]=2[CH:9]=1.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([CH:20]([CH3:21])[CH2:19][N:17]1[C:18]2[C:10]3[CH:9]=[C:8]([O:7][CH3:6])[CH:24]=[CH:23][C:11]=3[CH2:12][CH2:13][C:14]=2[CH:15]=[N:16]1)=[N+:33]=[N-:34]
Reactant: COc1ccc2c(c1)-c1c(cnn1CC(C)O)CC2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)-c1c(cnn1CC(C)N=[N+]=[N-])CC2
Yield: 60 %

Procedure:
0.89 ml (11.8 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.52 g (5.88 mmol) of (RS)-1-(4,5-dihydro-8-methoxy-1H-benz[g]indazol-1-yl)-propan-2-ol and 3.27 ml (23.5 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.76 g (11.8 mmol) of sodium azide and the reaction mixture was heated to 85° for 15 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 80 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1 g (60%) of (RS)-1-(2-azido-propyl)-4,5-dihydro-8-methoxy-1H-benz[g]indazole was obtained as a light yellow oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30]C1CCCCO1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCCCCC#CCCCCOC1CCCCO1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CC(C)(C)[Si](OCCCCCC#CCCCCO)(c1ccccc1)c1ccccc1
Yield: 72 %

Procedure:
Following the procedure reported to prepare analog 25, 1-(tert-butyldiphenylsilyloxy)-11-(tetrahydro-2H-pyran-2-yloxy)undec-6-yne was cleaved with a catalytic amount of PPTS to give the title compound (72%) as a colorless liquid. TLC:EtOAc/hexanes (3:7), Rf˜0.43; 1H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 3.62 (t, J=5.6 Hz, 4H), 2.06-2.22 (m, 4H), 1.64-1.50 (m, 10H), 1.04 (s, 9H); 13C NMR (100 MHz) δ 135.82, 134.33, 129.77, 127.84, 80.77, 80.11, 64.06, 62.69, 32.35, 32.10, 29.10, 27.12, 25.60, 25.33, 18.97, 18.78. HRMS calcd for C27H39O2Si [M+1]+ 423.2719, found 423.2718.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=1)[C:28](O)=[O:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH:21][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([CH3:22])[CH:24]=[N:25][CH:26]=3)=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Cc1cncc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cncc(C(=O)NNC(=O)c2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
To a yellow solution of 0.200 g (0.623 mmol) of 2-(2,6-Dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (Intermediate 1), 0.0854 g (0.623 mmol) of 5-methyl nicotinic acid, and 5 mL of DMF was added 0.1453 g (0.747 mmol) of EDCI, and 0.1010 g (0.747 mmol) of HOBt. Allowed to stir at r.t. for 18 h. Added 5 mL of water, EtOAc and filtered off solid, to give 0.1680 g of the title compound. Used directly in next reaction. MS (m/z) 440.0 M (+1), tR=1.00, Meth 10
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH2:28][C:29]([N:31]1[C:39]2[C:34](=[CH:35][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)=[O:30].C([O-])(O)=O.[Na+].N#N>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.O1CCOCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH2:28][C:29]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([C:2]3[C:10]4[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH:3]=3)=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)=[O:30]
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
Reactant: Nc1ncnc2c1c(Br)cn2CCN1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3c(c1)CCN3C(=O)Cc1cc(F)ccc1F)cn2CCN1CCOCC1
Temperature: 100 °C
Yield: 47.7 %

Procedure:
To 5-bromo-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.307 mmol), 1-[(2,5-difluorophenyl)acetyl]-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (159 mg, 0.399 mmol) in a 5 ml sealable vial was added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL). The mixture was then bubbled with N2 gas for 10 minutes then Pd(Ph3P)4 (35.4 mg, 0.031 mmol) was added. The mixture was again bubbled N2 gas for 5 minutes then capped and the reaction was heated at 100° C. overnight. The reaction was diluted with water (3 ml) then extracted with EtOAc (3×5 ml). The organics were then combined and washed with brine, dried over MgSO4, filtered and concentrated. The residue was then dissolved in 3 ml of DMSO and purified on HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 7% ACN/H2O, 0.1% TFA to 32% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. Then it was transferred into a 40 mL vial with MeCN then added water and freeze-dried to isolated 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (76 mg, 47.8% yield) as a white solid. LC-MS (ES) m/z=519.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[C:31]1=[O:38].Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:35]([CH:32]5[CH2:33][CH2:34][N:30]([CH3:29])[C:31]5=[O:38])=[O:36])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=[CH:27][CH:28]=1
Reactant: CN1CCC(C(=O)O)C1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (15.0 mg, 0.040 mmol; obtained from Example 5, Step D), 1-methyl-2-oxopyrrolidine-3-carboxylic acid (28.4 mg, 0.20 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (38.0 mg, 0.20 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (26.8 mg, 0.20 mmol), N-ethyl-N-isopropylpropan-2-amine (0.035 mL, 0.20 mmol) and CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material was consumed. Water (10 mL) was added, and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated, and the resulting residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford the desired product (14.8 mg, 74.1%). LRMS (APCI neg) m/e 502 (M−1). 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 7.78 (dd, J=12.4, 2.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 2H), 7.25-7.34 (m, 1H), 7.18 (m, 1H), 6.82 (d, J=8.8 Hz, 2H), 6.14 (m, 1H), 5.56 (s, 2H), 3.78 (s, 3H), 3.38-3.49 (m, 3H), 2.88 (s, 3H), 2.71 (s, 3H), 2.36-2.48 (m, 1H), 2.22-2.31 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][C:18]([CH3:25])([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH3:19])[C:14](Cl)=[O:15].C(N(CC)CC)C.C(OC(C)C)(C)C>O1CCOCC1>[CH3:12][N:13]([S:17][C:18]([CH3:19])([C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH3:25])[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: CC(C)C(=O)C(C)(C)SN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: CC(C)C(=O)C(C)(C)SN(C)C(=O)ON=C1SC(C)(C)C(=O)N1C
Yield: 39.6 %

Procedure:
Prepared as in Example I by reacting 2.94 g (0.0169 m) of 3,5,5-trimethyl-2-oximino-thiazolidin-4-one, 4.0 g (0.0169 m) of N-methyl-N-(2,4-dimethyl-3-oxo-2-pentanesulfenyl)carbamoyl chloride and 1.7 g (0.0169 m) of triethylamine in 200 ml of dioxane. The productcrystallized from isopropyl ether to yield 2.5 g of a white solid, m.p. 112°-114° C.
Reaction SMILES: COC1C=CC(C[S:10][C:11]2[N:12]([C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[CH:13]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]([CH3:17])[N:16]=2)=CC=1.FC(F)(F)C(O)=O.C(S)C>ClCCl>[CH3:17][C:15]1[NH:16][C:11](=[S:10])[N:12]([C:32]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[O:33])[CH:13]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:14]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(C(=O)c2ccc(OC)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCS
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=C(C)NC(=S)N(C(=O)c2ccc(OC)cc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 48 h

Procedure:
A solution of 1.5 g. (0.0026 mole) of 1,6-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-4-methyl-6-(3-nitrophenyl)-1-[(4-methoxyphenyl)carbonyl]-5-pyrimidinecarboxylic acid, ethyl ester in 15 ml. of dichloromethane is treated with 0.88 ml. (0.0113 mole) of trifluoroacetic acid and 0.38 g. (0.0059 mole) of ethanethiol. After stirring for 48 hours, the solvent is evaporated and the oil residue is triturated with isopropyl ether to form 0.91 g. of the title compound as a yellow solid, m. p. 130°-132°. TLC(silica gel; ethyl acetate hexane, 1:1) Rf =0.50.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:9])[C:5](=[O:8])[O:6][CH3:7].[Br:10][CH:11]([CH3:15])[C:12](Br)=[O:13]>>[Br:10][CH:11]([CH3:15])[C:12]([O:1][CH2:2][CH2:3][N:4]([CH3:9])[C:5](=[O:8])[O:6][CH3:7])=[O:13]
Reactant: COC(=O)N(C)CCO
Reactant: CC(Br)C(=O)Br
Product: COC(=O)N(C)CCOC(=O)C(C)Br

Procedure:
by using methyl N-(2-hydroxyethyl)-N-methyl-carbamate and 2-bromopropionyl bromide there is obtained methyl N-[2-(2-bromopropionyloxy)-ethyl]-N-methyl-carbamate, 1H-NMR (CDCl3, 60 MHz) 4.35 ppm (q, 1H), 4.32 ppm (t, 2H), 3.75 ppm (s, 3H), 3.58 ppm (t, 2H), 3.0 ppm (s, 3H), 1.82 ppm (d, 3H);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11](OCC)=[O:12])[N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:5]2=[CH:6][N:7]=1.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]2[N:29]([CH3:33])[C:30]([CH3:32])=[N:31][C:27]=2[CH:26]=1>>[CH3:33][N:29]1[C:28]2[CH:34]=[CH:35][C:25]([NH:24][C:11]([C:9]3[N:8]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[C:5]4=[CH:6][N:7]=[C:2]([F:1])[CH:3]=[C:4]4[CH:10]=3)=[O:12])=[CH:26][C:27]=2[N:31]=[C:30]1[CH3:32]
Reactant: Cc1nc2cc(N)ccc2n1C
Reactant: CCOC(=O)c1cc2cc(F)ncc2n1Cc1cccc(F)c1
Product: Cc1nc2cc(NC(=O)c3cc4cc(F)ncc4n3Cc3cccc(F)c3)ccc2n1C
Yield: 51.2 %

Procedure:
The process is performed according to the method described in step 2.4 of Example 2, starting with 0.3 g (0.95 mmol) of ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Example 2.3) and 0.183 g (1.14 mmol) of 5-amino-1,2-dimethylbenzimidazole. 0.21 g of expected compound is isolated.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:21]#[N:22]>>[C:21]([C:20]1[CH:23]=[CH:24][C:25]2[N:26]=[C:1]([C:3]3[CH:16]=[CH:15][C:6]([CH:7]=[C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]4=[O:14])=[CH:5][CH:4]=3)[NH:17][C:18]=2[CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Product: N#Cc1ccc2nc(-c3ccc(C=C4SC(=O)NC4=O)cc3)[nH]c2c1

Procedure:
5-Cyano-2-[4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenyl]benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 3,4-diaminobenzonitrile by following General Procedure 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C:17]1[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=1.Br[C:26]1[N:30]2[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:26]2[N:30]3[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:36])[CH3:37])=[N:34][C:29]3=[N:28][CH:27]=2)=[CH:4][C:3]=1[C:17]1[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Yield: 29 %

Procedure:
2′-Fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)-propan-2-ol in 29% yield using a similar procedure to that described in Example 3, step f, to give a yellow solid: mp 187° C.; 1H NMR (360 MHz, CDCl3) δ 1.71 (6H, s), 3.25 (1H, br s), 7.36-7.84 (5H, m), 8.09-8.16 (2H, m), 8.26 (1H, s), 8.76 (1H, s); MS (ES+) m/z 374 [M+H]+. Anal. Found: C, 67.34; H, 4.30, N. 18.47%. Required for C21H16FN5O: C, 67.55; H, 4.32; N, 18.76%.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([C@@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:15][C:16]1[CH:36]=[CH:35][C:34]([O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])=[CH:33][C:17]=1[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[C:2]([C:6]1[CH:7]=[C:8]([C@@H:12]([NH:14][C:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][C:17]2[CH:33]=[C:34]([CH:35]=[CH:36][C:16]=2[Cl:15])[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[C:20]([CH3:32])=[C:21]3[CH3:31])=[O:29])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: C[C@H](N)c1cccc(C(C)(C)C)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride the (S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH2:1](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[C:40]([NH:57][C@H:58]([C:61]([OH:63])=[O:62])[CH2:59][SH:60])(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55].C(Cl)(Cl)Cl>C(O)C.O>[C:40]([NH:57][C@H:58]([C:61]([OH:63])=[O:62])[CH2:59][S:60][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCSC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(=O)O
Reaction time: 20 h

Procedure:
4.8 g of docosanyl-p-toluenesulfonate and 5 g of potassium carbonate are added to 3.6 g of N-palmitoyl-(L)-cysteine in 50 ml of ethanol. The mixture is heated under stirring and in a nitrogen atmosphere at 80° for 20 hours. After evaporating to dryness the residue is acidified with 1 N HCl so as to obtain a pH of about 3 and then it is distributed between chloroform and water. After having dried and evaporated the chloroform layer a colourless crystalline residue is obtained, which is recrystallized from ethyl acetate. There is thus obtained the N-palmitoyl-S-docosanyl-(L)-cysteine.
Reaction SMILES: [CH2:1]([C:8]1[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([Br:17])[C:11]=2[O:10][C:9]=1[CH:19]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:22].II>C1COCC1>[CH2:1]([C:8]1[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([Br:17])[C:11]=2[O:10][C:9]=1[C:19]#[N:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)c2oc(C=O)c(Cc3ccccc3)c2c1
Reactant: [NH4+]
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Br)c2oc(C#N)c(Cc3ccccc3)c2c1
Reaction time: 8 h
Yield: 97 %

Procedure:
3-Benzyl-7-bromo-5-methyl-benzofuran-2-carbaldehyde (2.61 gm, 7.93 mmol) was added to a mixture of THF (10 ml) and concentrated ammonium hydroxide (80 ml). Iodine (2.2 g, 8.67 mmol) was added and the grey slurry was stirred overnight. Additional THF (20 ml), ammonium hydroxide (20 ml), and iodine (0.2 g, 0.8 mmol) were added, and the mixture stirred for 30 minutes. The reaction mixture was quenched by addition of aqueous 10% sodium thiosulfate (20 ml) and brine (20 ml). The mixture was extracted with diethy ether, and the combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3-benzyl-7-bromo-5-methyl-benzofuran-2-carbonitrile (2.5 g, 97% yield). (M+H)+ 327.