Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][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][O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23].[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:18]([O:19][CH2:20][CH:21]([CH2:22][O:23][C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:24])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
51.69 Grams (150 mmol) of batylalcohol and 62.73 g (225 mmol) freshly recrystallized tritylchloride are dissolved at 35° C. in 350 ml methylene chloride. (Note: It is recommended that the tritylchloride be freshly recrystallized from halpasol, tradename for a petroleum ether fraction, b.p. 100°-120° C.). During 15 minutes, 22.77 g (225 mmol; 31.38 ml) triethylamine is added dropwise to the stirred solution at 30°-35° C. (cooling with a water bath). The reaction is continued for six hours at ambient temperature. (Note: It is recommended that a control TLC be done to make sure that the reaction is complete). The solution is then washed with 300 ml of a NaHCO3 solution (1%), dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The oily residue (155 g) is dissolved in 660 ml acetonitrile by warming up to 70° C. with stirring. After cooling to room temperature the title product crystallizes (preferentially after adding a few seed crystals). Crystallization is completed by standing overnight at ambient temperature. The crystallizate is filtered off to yield 82.5 g (93.7%) of crude product (m.p. 53°-55° C.) which can be used for the following step without purification. Recrystallization from halpasol (310 ml) yields 71 g (80%) of pure tritylbatylalcohol.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][O:9][C:10](=[O:46])[N:11]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37](N)[CH:36]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33].[ClH:47]>C(#N)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:46])[N:11]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([Cl:47])[CH:36]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33]
Reactant: Cl
Reactant: COC(=O)N(Cc1cc(N)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)N(Cc1cc(Cl)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of CuCl2 (11.9 mg, 0.09 mmol) in acetonitrile (1 mL) was added t-butyl nitrite (11 μL, 0.092 mmol). Next, the solution was cooled to 0° C. and methyl[3-amino-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (41 mg, 0.074 mmol) (Example 33) was added as a solution in acetonitrile (1.5 mL). The reaction was slowly warmed to room temperature. After stirring at room temperature for 2 hours, the mixture was diluted with EtOAc (30 mL) and poured into 20% HCl (5 mL). The organic extracts were washed with 20% HCl (2×5 mL), H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 5% to 80% EtOAc/hexanes afforded methyl[3-chloro-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.65 (15% EtOAc/hexanes). LCMS=574.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.68 (s, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.30 (s, 1H), 7.08-7.05 (m, 4H), 6.83 (d, J=2.5 Hz, 1H), 6.60 (d, J=8.5 Hz, 1H), 4.35 (broad singlet, 3H), 4.01 (broad singlet, 1H), 3.36 (s, 3H), 3.26 (s, 3H), 2.74 (m, 1H), 1.16 (d, J=7.0 Hz, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[N:21]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:8].O.[O-:33][C:34]#[N:35].[K+]>N1C=CC=CC=1>[NH:1]([CH2:2][CH2:3][CH2:4][N:5]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[N:21]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:8])[C:34]([NH2:35])=[O:33]
Reactant: N#C[O-]
Reactant: COc1ccc(CCNC(=O)CN(CCCN)c2cc(C)nc(-n3ccnc3)n2)cc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(CCNC(=O)CN(CCCNC(N)=O)c2cc(C)nc(-n3ccnc3)n2)cc1
Temperature: 80 °C

Procedure:
To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide (135 mg, 0.32 mmol) (a compound of formula (Yc6)) in pyridine (1.5 mL) was added water (1.5 mL) solution of potassium cyanate (64 mg, 0.76 mmol). The mixture was stirred and heated in an oil bath at 80° C. overnight. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate fractions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (9:1 CH3CN/NH4OH) to afford 2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide, a compound of formula (Yc9); as a white solid; NMR (DMSO-d6, 90 C) 8.4 (s, 1), 7.8 (s, 1), 7.05 (d, 2), 7.0 (s, 1), 6.75 (d, 2), 6.4 (s, 1), 4.1 (s, 2), 3.7 (s, 3), 3.5 (m, 2), 3.25 (m, 2), 3.05 (m, 2), 2.65 (t, 2), 2.3 (s, 3), 1.7 (m, 2) ppm.
Reaction SMILES: O.O.[N+:3]([C:6]1[CH:13]=[CH:12][C:9]([O:10][Na])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl.[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19]Cl)[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C(C)=CC=CC=1>[CH2:15]([N:17]([CH2:21][CH2:22][O:10][C:9]1[CH:12]=[CH:13][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCN(CC)CCCl
Reactant: O=[N+]([O-])c1ccc(O[Na])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Yield: 79.5 %

Procedure:
4-Nitrophenoxy sodium dihydrate (29.39 g), 2-(diethylamino)ethylchloride hydrochloride (25.60 g), potassium carbonate (30.17 g) and water (60 ml) were added into xylene (100 ml) and the mixture was heat-refluxed for 2 hours while mixing and continuously removing water by azeotropic distillation. After reaction, insolubles were removed by filtration. Filtrate was added with ethyl acetate (100 ml) and extracted 3 times with 1N HCl (100 ml). Aqueous layer was adjusted to pH 10 with 1N sodium hydroxide and oily substance separated was extracted 3 times with ethyl acetate (100 ml). Ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated to obtain N,N-diethyl-2-(4-nitrophenoxy)ethylamine (28.19 g) as color-less oily substance.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[C:58]([CH3:63])=[N:59][O:60][C:61]=1[CH3:62])=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[C:58]([CH3:63])=[N:59][O:60][C:61]=2[CH3:62])=[O:56])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: Cc1noc(C)c1N=C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1NC(=O)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 4-isocyanato-3,5-dimethylisoxazole as the starting materials in 50% yield. LCMS for C30H34ClN8O3 (M+H)+: m/z=589.1.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C>C(O)(C)(C)C>[C:5]1([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: O=C(O)Cc1ccccc1
Yield: 113.5 %

Procedure:
A mixture of 8.3 g of 2-tosyltropone, 4.5 g of p-aminophenylacetic acid and 9 ml of triethylamine in 200 ml of tert-butylalcohol was refluxed for 24 hours. The mixture was concentrated and acidified with 2 N hydrochloric acid, followed by extraction with dichloromethane. The dichloromethane solution was extracted with a saturated sodium bicarbonate aqueous solution. The aqueous layer was acidified and extracted with dichloromethane. The dichloromethane solution was washed with water and dried over anhydrous magnesium sulfate and evaporated to give a yellow crystalline solid, which was recrystallized from ethanol to yield 4.6 g of p-(2-troponylamino) phenylacetic acid; m.p. 175°-176° C.; Analysis--Calculated for C15H13NO3 : C 70.58%, H 5.13%, N 5.49%; Found: C70.34%, H 5.30%, N 5.55%.
Reaction SMILES: [F-:1].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.C(#N)C.[N+]([C:35]1[CH:36]=[C:37]2[C:42](=[O:43])[O:41][C:39](=[O:40])[C:38]2=[CH:44][CH:45]=1)([O-])=O>C(Cl)Cl>[F:1][C:35]1[CH:36]=[C:37]2[C:42](=[O:43])[O:41][C:39](=[O:40])[C:38]2=[CH:44][CH:45]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: [F-]
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Solvent: ClCCl
Product: O=C1OC(=O)c2cc(F)ccc21
Temperature: 82 °C
Yield: 75.3 %

Procedure:
To a reaction vessel equipped with a reflux condenser, nitrogen inlet and oil bath were introduced 2.008 grams (0.035 mol) anhydrous potassium fluoride, 0.458 gram (0.0013 mol) dibenzo-18-crown-6, and 20 ml. dry acetonitrile. This mixture was refluxed at about 82°C. for 30 minutes, and thereafter 3.011 grams (0.016 mol) 4-nitrophthalic anhydride was added and the mixture refluxed for an additional 43 hours. After cooling to room temperature, methylene chloride was added to the reaction mixture, and the latter filtered to remove solid material. Concentration of the filtrate under vacuum yielded 2 grams of 4-fluorophthalic anhydride containing a small amount of the dibenzo-18-crown-6. To remove this latter crown ether, the material was dissolved in aqueous potassium hydroxide, extracted with ethyl acetate, and acidified with hydrochloric acid to a pH 1. Extraction with ethyl acetate yield 1.195 grams (42% yield) of pure 4-fluorophthalic acid which can be dehydrated to yield 4-fluorophthalic anhydride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[C:23]([NH2:28])[C:24]([NH2:27])=[CH:25][CH:26]=2)[CH2:17][CH2:16]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>CN(C=O)C>[NH2:28][C:23]1[CH:22]=[C:21]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)[CH:26]=[CH:25][C:24]=1[NH:27][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][N:9]=1)=[O:13]
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC(=O)c3n[nH]c4ncc(Br)cc34)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid Compound 1c (2.095 g, 8.66 mmol), 4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine Compound 14a (1.79 g, 8.68 mmol), HATU (3.29 g, 8.66 mmol) and DIPEA (4 mL, 28.7 mmol) in DMF (70 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (10% to 90% of ethyl acetate in hexanes) to yield 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid [2-amino-4-(4-methyl-piperazin-1-yl)-phenyl]-amide Compound 14b (2 g, 54% yield) as a brown powder. 1H NMR (300 MHz, CD3OD) δ 8.81 (d, 1H, J=2.1 Hz), 8.66 (d, 1H, J=2.1 Hz), 7.42 (d, 1H, J=8.7 Hz), 7.11 (dd, 1H, J=2.7, 8.7 Hz), 7.03 (d, 1H, J=2.7 Hz), 3.92 (b, 2H), 3.65 (b, 2H), 3.31 (b, 2H), 3.16 (b, 2H), 2.81 (s, 3H); MS (ESI) m/z: 431 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19]S(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]([NH2:34])(=[O:33])[CH:31]=C>>[C:1]([O:5][C:6]([NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:31][C:30]([NH2:34])=[O:33])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Reactant: C=CC(N)=O
Product: CC(C)(Cc1c[nH]c2c(C=CC(N)=O)cccc12)NC(=O)OC(C)(C)C

Procedure:
3-[3-(2-tert-Butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-acrylamide is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and acrylamide as described for the preparation of Amine 23 (98%). FDMS m/e 356.2 (M++1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]1=[O:20].[NH2:22][OH:23].[OH-].[Na+]>C1COCC1>[OH:23][NH:22][C:3](=[O:2])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]1=[O:20]
Reactant: COC(=O)CC1Cc2ccccc2N(CCC(C)C)C1=O
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CCN1C(=O)C(CC(=O)NO)Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The crude [1-(3-methyl-butyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester obtained in the previous step is dissolved in 0.5 mL of anhydrous THF. Freshly prepared NH2OH (0.77 M in MeOH) (0.44 mL) (also containing 0.77M NaOH) is then added and the mixture is stirred at room temperature for 12 hours. The final product N-hydroxy-2-[1-(3-methyl-butyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetamide is obtained by preparative LC/MS using 1 to 99% ACN as gradient. 1H NMR (400 MHz, MeOD): δ 7.29 (t, 1H), 7.20 (d, 1H), 7.11 (d, 1H), 7.04 (t, 1H), 3.97 (m, 2H), 3.02-2.89 (m, 2H), 2.77-2.65 (m, 2H), 2.17 (dd, 1H), 1.65 (m, 1H), 1.50 (m, 2H), 0.97 (2d, 6H). MS: (ES+): 291.3 [M+1].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:23][C:24]1[C:25]([Cl:30])=[N:26][CH:27]=[CH:28][CH:29]=1>C1COCC1>[Cl:30][C:25]1[C:24]([CH2:23][CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: Clc1ncccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ncccc1CC(c1cccnc1)c1cccnc1
Reaction time: 0.17 h

Procedure:
A solution of bis-(3-pyridyl)methane in 150 mL of THF was cooled to −30 C. LDA (1.5 M solution in cyclohexane, 29.4 mL) was added dropwise to give a dark red solution containing some red solid matter. The mixture was then stirred at 0 C for 10 min. A solution of 3-(bromomethyl)-2-chloropyridine in 50 mL of THF was added dropwise over 25 min, and the reaction was stirred at 0 C for 2 h, after which the reaction was quenched by adding saturated aqueous NH4Cl. The mixture was partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (3×), and the combined organic solutions were dried (Na2SO4) and concentrated. Flash chromatography gave 9.1 g of 2-chloro-3-(2,2-dipyridin-3-ylethyl)pyridine as a red, viscous liquid.
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[Cl:18][C:19]1[C:20]([CH3:26])=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>CS(C)=O>[Cl:18][C:19]1[C:20]([CH3:26])=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH:22][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Reactant: Cc1c(N)cccc1Cl
Solvent: CS(C)=O
Product: Cc1c(Cl)cccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 3-chloro-2-methylaniline (0.026 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 329 (M+).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].[C:7]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])(OCC)=O>O>[C:13]1(=[O:22])[N:12]([C@@H:7]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:1]([OH:2])=[O:4])[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (+)-L-ε-hydroxynorleucine [prepared according to the procedure of Bodanszky et al., J. Med Chem., 1978, 21, 1030-1035] (1.030 g., 7.0 mmol.) and sodium carbonate (745 mg., 7.0 mmol.) in water (12 ml.) was treated with N-carbethoxy-phthalimide (1.495 g., 7.0 mmol.) and the mixture was stirred at room temperature for 2 hours. The solution was filtered, cooled to 0° C., and acidified with 6N hydrochloric acid to afford a white precipitate. The solid was collected by filtration and dried in vacuo at 80° C. for one hour to give 1.297 g. of the title compound; m.p. 162°-1630° C.; [α]D =-35.7° (c=1.3, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20](Cl)=[O:21].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][N:25]=[C:17]([Cl:16])[CH:18]=2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1C(F)(F)F
Reactant: O=C(Cl)c1ccnc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NS(=O)(=O)c1ccc(Cl)cc1C(F)(F)F)c1ccnc(Cl)c1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
2.6 g (0.01 mol) of 4-chloro-2-trifluoromethylbenzenesulfonamide were dissolved in 20 ml of pyridine, 2-chloroisonicotinoyl chloride was added dropwise at room temperature. Agitation was then continued for 2 hr. at the same temperature. The reaction mixture was acidified by adding aqueous hydrochloric acid, and the precipitate thus formed was extracted by ethyl acetate. The organic layer obtained was dried and then concentrated to precipitate crude crystals, which were recrystallized by solvent mixture of n-hexane and ethyl acetate to produce 3.4 g (yield: 85.1%) of N-(4-chloro-2-trifluoromethylphenylsulfonyl)-2-chloroisonicotinamide as white crystals.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[N:7]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:8]([CH:12]([CH3:14])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.N([O-])=[O:24].[Na+]>S(=O)(=O)(O)O.O.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:7]2[C:6](=[O:22])[C:5]3[C:10](=[CH:11][C:2]([OH:24])=[CH:3][CH:4]=3)[N:9]=[C:8]2[CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=1
Reactant: CC(C)c1nc2cc(N)ccc2c(=O)n1-c1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)c1nc2cc(O)ccc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
To a suspension of the compound of Example 1 (778 mg, 2.479 mmol) in concentrated sulphuric acid/water 972 μL/1.4 mL, cooled to ice bath temperature, is added a solution of sodium nitrite (188 mg) in water (680 μL). The mixture is stirred for 45 minutes at 0-5° C. (internal temperature) and then added to sulphuric acid/water 3/2 (5 mL), pre-heated to 150° C. After stirring for 15 minutes, the mixture is allowed to cool to room temperature, filtered and extracted with EtOAc (3×). The combined EtOAc extracts are washed with water, dried (Na2SO4) and evaporated to a yellow-orange solid. Purification by automated flash chromatography (gradient elution: EtOAc/hexane 0-25%) provides the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCN(C)CC2)CCN(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (0.57 g, 2.2 mmol) was taken in DCM, cooled to 0° C., oxalyl chloride (0.228 mL, 2.6 mmol) was added, followed by the addition of DMAP (catalytic amount) and stirred for 1 h at RT. Solvent was evaporated under nitrogen, N-methyl piperazine (0.269 mg, 24 mmol) and DMAP (80 mg) in DCM was added slowly drop wise at RT (under nitrogen) and stirred at RT for 30 min. Reaction mixture was quenched with water, neutralized with 10% NaHCO3 solution and extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. Crude product was purified by reverse phase chromatography to afford 100 mg of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-methylpiperazin-1-yl)ethanone as TFA salt.