Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][NH2:14])[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[N:15]#[C:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:11]([O:10][C:9]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]2[N:7]([C:16]([NH2:15])=[N:14][N:13]=2)[N:8]=1)[CH3:12]
Reactant: N#CBr
Reactant: CCOc1cc(NN)nnc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOc1cc2nnc(N)n2nc1OCC
Reaction time: 8 h
Yield: 63.9 %

Procedure:
(5,6-Diethoxy-pyridazin-3-yl)hydrazine (W3.120; 50 mg) was initially charged in a mixture of ethanol (3.5 ml) and water (0.75 ml) at RT while stirring. Thereafter, cyanogen bromide (55 mg, dissolved in 0.75 ml of ethanol and 0.15 ml of water) was cautiously added dropwise. After stirring for 7 h, the mixture was left to stand overnight. Thereafter, a further 2 equivalents of cyanogen bromide, dissolved in 0.75 ml of ethanol and 0.15 ml of water, were added and the mixture was stirred further at RT for 2 h and then at 55° C. for 8 h. After cooling, the solvent was drawn off and the residue was admixed with water. After it had been alkalized with saturated potassium carbonate solution, it was extracted four times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The residue was purified by means of preparative HPLC (met. A). The clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted four times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 36 mg of the title compound were obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[C:5](=[O:6])[NH:4][C@@H:3]1[CH2:7][N:8]1[N:12]=[C:11]([CH2:13][N:14]([C:22]([N:31]2[CH2:34][CH:33]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]2)=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[N:9]1.[CH:44]([O:57][C:58]([C:60]1([O:63]/[N:64]=[C:65](/[C:69]2[N:70]=[C:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[S:72][CH:73]=2)\[C:66](O)=[O:67])[CH2:62][CH2:61]1)=[O:59])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:17]([O:16][C:15]([N:14]([CH2:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C@@H:3]2[C@H:2]([NH:1][C:66](=[O:67])/[C:65](=[N:64]\[O:63][C:60]3([C:58]([O:57][CH:44]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:59])[CH2:62][CH2:61]3)/[C:69]3[N:70]=[C:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[S:72][CH:73]=3)[C:5](=[O:6])[NH:4]2)[N:12]=1)[C:22]([N:31]1[CH2:34][CH:33]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]1)=[N:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:21])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N=C(N1CC(CNC(=O)OC(C)(C)C)C1)N(Cc1cnn(C[C@H]2NC(=O)[C@H]2N)n1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(N1CC(CNC(=O)OC(C)(C)C)C1)N(Cc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)n1)C(=O)OC(C)(C)C
Yield: 75.9 %

Procedure:
Prepared in analogous manner to example 126 step 3, using tert-butyl ((2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl)((3-(((tert-butoxycarbonyl)amino)methyl)azetidin-1-yl)((tert-butoxycarbonyl)imino)methyl)carbamate (460 mg, 0.76 mmol), (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (407 mg, 0.76 mmol), DMF (8 mL), DCM (8 mL), HATU (345 mg, 0.91 mmol) and DIPEA (0.33 μL, 1.89 mmol). The crude residue was purified via silica gel chromatography (EtOAc-heptane, 0-100%) to afford the title compound (0.65 g, 76%). LCMS: Rt=1.15 min, m/z=1127.9 (M+1) Method 2m_acidic.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CCC(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of ethyl 3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)propanoate (0.61 g, 1.2 mmol) in tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1N sodium hydroxide solution (3 ml). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-diisopropyl ether to give 3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)propanoic acid (0.52 g, 91.2%) as crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[O:11][CH3:12].C([Li])CCC.[Br:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][CH:20]=1.BrC1C=CC(C(Cl)=O)=CC=1.Cl.CNOC.CN1CCOCC1.S([O-])(O)(=O)=O.[K+]>C1COCC1.CCCCCC.C(OCC)(=O)C>[Br:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([C:6]2[C:7]([F:8])=[C:2]([F:1])[C:3]([O:11][CH3:12])=[C:4]([F:10])[C:5]=2[F:9])=[O:24])=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Reactant: COc1c(F)c(F)cc(F)c1F
Agent: CNOC
Agent: Cl
Agent: O=C(Cl)c1ccc(Br)cc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1c(F)c(F)c(C(=O)c2ccc(Br)cc2)c(F)c1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
A solution of 5.4 g of 2,3,5,6-tetrafluoro-anisole in 80 ml of absolute THF is cooled to −78° C. and treated with 20.6 ml of 1.6M butyllithium in hexane within 15 min. After 20 min. 7.4 g of 4-bromo-N-methoxy-N-methylbenzamide (prepared from 4-bromo-benzoyl chloride and N,O-dimethylhydoxylamine, hydrochloride with N-methylmorpholine as the base) in 10 ml of THF are added dropwise and the mixture is stirred at −78° C. for 2 hrs. The reaction solution is poured into cold 10% potassium hydrogen sulphate solution/ethyl acetate and the organic phase is washed with water and 10% sodium chloride solution and dried. After crystallization from cyclohexane there are obtained 5.8 g of (4-bromo-phenyl)-(2,3,5,6-tetrafluoro-4-methoxy-phenyl)-methanone, m.p. 80-82° C.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[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][CH3:18].[O-2].[Zn+2:22]>>[C:1]([O-:20])(=[O:19])[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][CH3:18].[Zn+2:22].[C:1]([O-:20])(=[O:19])[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][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 60 °C

Procedure:
A slight stoichiometric excess of stearic acid was added to the zinc oxide aqueous slurry. It was heated with agitation to 60° C. to melt the stearic acid. As the melt temperature is approached, the stearic acid reacted with the zinc oxide to produce fine particle size zinc stearate. Fine particle size zinc stearate is used in the rubber and paint industries.
Reaction SMILES: FC1C=CC([N+]([O-])=O)=CC=1N.N1C=CC=CC=1.C(Cl)(=O)C1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:29]=1[NH:37][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.CO.[Pd].C1COCC1.CO>[NH2:34][C:31]1[CH:32]=[CH:33][C:28]([F:27])=[C:29]([NH:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:30]=1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)c1ccccc1
Agent: [Pd]
Agent: Nc1cc([N+](=O)[O-])ccc1F
Solvent: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(F)c(NC(=O)c2ccccc2)c1
Yield: 91 %

Procedure:
6-[N-(3-Benzamido-4-fluorophenyl)amino]-1-(2-trimethylsilanyl-ethoxymethyl-3-E-styryl1H-indazole was converted to Example 47 in a similar manner to that described for Example 11. 1H NMR (300 MHz, DMSO-d6) δ 12. (s, 1H, 10.0 (s, 1H), 8.38 (bs, 1H), 8.02 (d, 1H, J=8.78), 7.98 (d, 2H, J=6.87 Hz), 7.69 (d, 2H, J=7.27 Hz), 7.48-7.61 (m, 4H), 7.45 (s, 2H), 7.40 (t, 2H, J=7.28 Hz), 7.53-7.30 (t, 2H, J=7.28 Hz), 7.53-7.30 m, 2H), &.07 (d, 1H, J=1.55 Hz), 7.03 (m, 1H), 6.95 (dd, 1H), J=8.79 Hz, J=1.85 Hz), MS (ESI+) [M+H]/z Calc'd 449, found 449. Anal. Calc'd: C, 74.98. H, 4.72. N, 12.193 Found: C, 74.29. H, 4.76. N, 12.12. The starting material was prepared as follows: To a solution of 2-fluoro-5-nitro-phenylamine (3.12 g, 20 mmol) in dichloromethane (20 ml) at 23° C. under argon was added pyridine (1.94 ml, 24 mmol) and benzoyl chloride (2.8 ml, 24 mmol). After 45 minutes a white precipitate formed. The reaction mixture was concentrated in-vacuo then diluted with water and filtered to give a white solid which was re-suspended in MeOH and filtered again giving N-(2-fluoro-5-nitro-phenyl)-benzamide (4.86 g, 93%). H NMR (300 MHz. CDCl3) δ 9.48 (dd, 1H. 3=6.8 Hz, J=2.81 Hz), 8.17 (bs, 1H), 8.03 (m, 1H), 7.92 (m, 2H), 7.52-7.65 (m, 3H), 7.31 (d, 1H, J=9.2 Hz). A mixture of N-(2-fluoro-5-nitro-phenyl)-benzamide (4.86 g. 18.7 mmol) and 10% Pd/C (486 mg) in a 1:1 mixture of THF-MeOH (80 ml) was hydrogenated at 23° C. After 2.5 h the reaction mixture was filtered through celite and concentrated to give N-(5-Amino-2-fluoro-phenyl)-benzamide (3.92 g, 91%). MS (ESI+) [M+H]/z Calc'd 231, found 231. 6-[N-(3-Benzamido-4-fluorophenyl)amino]-1-(2-trimethylsilanyl-ethoxymethyl-3-E-styryl 1H-indazole was prepared in a similar manner as Example 48(a), step (iii) except that N-(5-amino-2-fluorophenyl)benzamide, and the compound prepared in Example 14, step (i) were used as starting materials. 1H NMR (300 MHz, CDCl3) δ 8.38 (dd, 1H, J=6.84 Hz, J=2.73 Hz), 8.09 (d, 1H, J=3.08 Hz), 7.86-7.91 (m, 3H), 7.48-7.61 (m, 5H), 7.28-7.45 (m, 4H), 7.19 (d, 1H, J=1.7 Hz), 7.08 (dd, 1H, J=10.48 Hz), 6.906.96 (n, 2H), 6.03 (bs, 1H), 5.66 (s, 2H), 3.62 (t, 2H, J=8.14 Hz), 0.91 (t, 2H, J=8.32 Hz), 0.0 (s, 9H). MS (ESI+) [M+H]/z Calc'd 579, found 579. Anal. Calc'd: C, 70.56. H, 6.10. N. 9.68. Found: C, 20.26. H, 6.08. N, 9.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[CH2:14]1[C@@H:17](C(O)=O)[NH:16][CH2:15]1>CS(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[N:16]3[CH2:17][CH2:14][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Cl)c2C(=O)N2CC[C@@H]12

Procedure:
11.3 g (0.057 mol) of 6-chloro-isatoic acid anhydride and 5.78 g (0.057 mol) of L-azetidine-2-carboxylic acid are heated to 125° in 50 ml of dimethyl sulphoxide for 2 hours. The mixture is subsequently evaporated to dryness in a high vacuum and the residue obtained is heated to 150° for 2 hours. By chromatography on silica gel while eluting with ethyl acetate there is obtained (S)-5-chloro-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione of melting point 225°-228°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)c1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 199 μl of bromobenzene (1.88 mmol) and 361 μl of benzenesulphonyl chloride (2.83 mmol) in 4 ml of trifluoroacetic acid there are added, in succession, 83 mg of indium chloride (0.376 mmol) and then, dropwise, 25 μl of trifluoromethanesulphonic acid. The reaction mixture is stirred for 2 hours at 70° C. and is then returned to ambient temperature and diluted with ice-cold water. After rendering alkaline to pH 10 by adding concentrated sodium hydroxide solution, the reaction mixture is extracted with CH2Cl2. The organic phases are collected, washed with saturated NaCl, dried (MgSO4) and evaporated under reduced pressure to yield the title product in the form of a white solid.
Reaction SMILES: [CH:1]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:19][Cl:20].O>C1COCC1.C1COCC1.CCCCCC>[Cl:20][CH2:19][C:1]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1CCCCCC1
Reactant: ClCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(CCl)CCCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
A solution of cycloheptanecarbonitrile (12.3 g), 100 mmol) in THF (50 ml) was added dropwise to a well stirred solution of lithium diisopropylamide (105 mmol) in THF/hexane (75 ml/60 ml) under nitrogen, keeping the temperature at -65°. After 1 h, the solution was allowed to warm to ambient temperature and added dropwise to a well stirred solution of bromochloromethane (32.5 ml; 500 mmol) in THF (50 ml) under nitrogen keeping the temperature between -50° and -60°. After 10 min, the solution was allowed to warm to ambient temperature, poured into water (250 ml) and the aqueous mixture extracted with chloroform (3×150 ml). The extracts were washed with 2N-HCl (2×50 ml), saturated aq. NaHCO3 (100 ml), and water (100 ml), then dried (MgSO4) and evaporated under reduced pressure to give a brown oil (18.0 g). Distillation gave the title compound (12.65 g), b.p. 78°-80° at 0.25 mmHg.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11](Br)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(B(O)O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cc(Br)cc(C=C(c2ccccc2)c2ccccc2)c1
Reactant: OB(O)c1cccc2ccccc12
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: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cc(C=C(c2ccccc2)c2ccccc2)cc(-c2cccc3ccccc23)c1
Yield: 59.6 %

Procedure:
Under an atmosphere of argon, 1-(2,2-diphenylvinyl)-3,5-dibromo-benzene (8.3 g, 20 mmole), 1-naphthaleneboronic acid (3.4 g, 20 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.46 g, 0.4 mmole, 2% Pd) were dissolved into toluene (50 ml). To the obtained solution, a 2 M aqueous solution of sodium carbonate (30 ml, 60 mmole, 3 eq) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloro-methane and hexane+10% dichloromethane, successively) and a white glass solid (5.5 g, 60%) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:10](=O)[CH2:11][CH2:12][CH3:13]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:11][CH2:12][CH3:13])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCC=O
Solvent: CO
Solvent: O
Product: CCCC(c1c[nH]c2ccccc12)c1c[nH]c2ccccc12

Procedure:
282 mg of indole (2.4 mmol) were dissolved in 10 ml of CH3OH and 5 ml of H2O; 72 mg (1 mmol) of butyraldehyde and 240 mg of dysprosium triflate-(CF3SO3)3Dy-(0.393 mmol) were added.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:15]=[N:14][C:7]2[N:8]=[C:9]([NH2:13])[N:10]=[C:11]([NH2:12])[C:6]=2[C:5]=1[CH3:16].C(P(CCCC)CCCC)CCC.[C:30]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)(=O)[CH2:31][CH3:32].[H-].[Na+]>>[NH2:13][C:9]1[N:10]=[C:11]([NH2:12])[C:6]2[C:5]([CH3:16])=[C:4]([CH2:3][CH2:32][CH:31]=[CH:30][C:34]3[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=3)[CH:15]=[N:14][C:7]=2[N:8]=1
Reactant: Cc1c(CBr)cnc2nc(N)nc(N)c12
Reactant: CCC(=O)c1ccc(C(=O)OC)cc1
Agent: Br
Agent: CCCCP(CCCC)CCCC
Agent: [H-]
Product: COC(=O)c1ccc(C=CCCc2cnc3nc(N)nc(N)c3c2C)cc1
Temperature: 21.5 °C
Reaction time: 44 h

Procedure:
A solution of the bromomethyl compound 1 (3.13 g, 8.24 mmol) and tributylphosphine (5.00 g, 24.7 mmol) in Me2SO (200 mL) was kept 20 hours at 20°-23° C., then gradually warmed during 90 minutes to 55° C. for 30 minutes, and cooled to 20-23° C. Methyl 4-(propionyl)benzoate (1.58 g. 8.22 mmol) was then added, followed by sodium hydride (660 mg of 60% dispersion in oil, 16.5 mmol). Complete solution occurred readily. After 44 hours at 20°-23° C., the solution was heated at 70°-75° C. for 64 hours. Removal of the Me2SO by distillation in vacuo (less than 1 mm, bath to 55° C.) followed. The syrupy residue was stirred with Et2O until the yellow solid that formed was dispersed. The solid was collected with the aid of Et2O, air dried, then stirred thoroughly with H2O before it was again collected and dried in vacuo (78° C.) over NaOH pellets and P2O5) Crude 3 (2.31 g, 77% crude yield) was combined with a sample from another run and the combined batch was purified by flash chromatography on silica gel (230-400 mesh) using elution by CHCl3 -MeOH (9:1). Fractions found by TLC to be homogeneous (UV detection) were pooled and evaporated to give pure 3. The purified material amounted to 50% recovery of material applied to the column. Spectral data: mass, m/z 364, (MH+) for C20H21N5O2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([NH:15][C:16](=[O:22])[CH2:17][O:18][CH2:19][CH2:20]Cl)[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:22])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(NC(=O)COCCCl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3=O)ccc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A mixture of 2-bromo-7-(2-(2-chloroethoxy)acetamido)-5H-pyrido[3,2-b]indole-4-carboxamide (40 mg, 0.094 mmol) and potassium carbonate (27 mg, 0.20 mmol) in acetonitrile (2.5 mL) was stirred at 100° C. for 3 hr. The solvent was removed and preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, 10-60% B at 42 mL/min over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH left 2-bromo-7-(3-oxomorpholino)-5H-pyrido[3,2-b]indole-4-carboxamide (30 mg, 0.073 mmol, 78% yield) as a yellow solid. MS (ESI) m/z 389.02 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.84 (1H, br. s.), 8.06-8.32 (1H, m), 7.89 (2H, br. s.), 7.52-7.76 (2H, m), 7.23 (1H, br. s.), 4.16-4.36 (2H, m), 3.94-4.13 (2H, m), 3.74-3.90 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])=[N:9][CH:10]=2)[N:7]=1.C(N(CC)CC)C.[H][H]>[Pd].C(OCC)(=O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[CH:2][CH:3]=[CH:4][C:5]2=[CH:10][N:9]=1
Reactant: [H][H]
Reactant: Fc1ccccc1Cc1ncc2ccc(Cl)nn12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1ccccc1Cc1ncc2cccnn12

Procedure:
2.004 g of palladium on carbon (5%) were initially charged under argon, and 20.04 g (76.58 mmol) of the compound obtained in Example 3A in ethyl acetate (750 ml) were then added. 21.348 ml (153.159 mmol) of triethylamine were then added, and the reaction mixture was hydrogenated at standard hydrogen pressure and 20° C. for 16 hours. The same amount of catalyst as indicated above was then added, and the reaction mixture was hydrogenated at standard hydrogen pressure and 20° C. for another night. The mixture was then filtered through Celite, the filter cake was washed with ethanol and the filtrate was concentrated and dried under high vacuum. This gave 22.79 g of the target compound (about 100% of theory, contaminated with triethylamine).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([N:17]([CH3:28])[C@H:18]([C:20]([C@:22]([CH3:27])([OH:26])[C:23]([OH:25])=O)=[O:21])[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[CH2:10]([N:17]([CH3:28])[C@H:18]([C:20]([C@:22]([CH3:27])([OH:26])[C:23]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:25])=[O:21])[CH3:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C1CCNCC1
Reactant: C[C@@H](C(=O)[C@](C)(O)C(=O)O)N(C)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](C(=O)[C@](C)(O)C(=O)N1CCCCC1)N(C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
5.4 g (41.4 mmol) of N,N-diisopropylethylamine (Hünig's base) and 5.3 g (20.7 mmol) of bis(2-oxo-3-oxazolidinyl)-phosphonium acid chloride (BOP-Cl) are added at 0° C. to a solution of 5.0 g (18.8 mmol) of N-benzyl-N-methyl-L-alanyl-D-lactic acid and 1.6 g (20.7 mmol) of piperidine in 150 ml of methylene chloride, and the mixture is stirred at 0° C. for two hours and then at room temperature for 18 hours. The residual crude product is chromatographed on a silica gel column (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane:ethyl acetate (3:1). 3.5 g (55.8% of theory) of N-benzyl-N-methyl-L-alanyl-D-lactic acid piperidide are obtained.