Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[C:29]([N+:36]([O-:38])=[O:37])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[C:29]([N+:36]([O-:38])=[O:37])[CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5cccc([N+](=O)[O-])c5n4)cc3CC[C@@H]12
Yield: 54.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-8-nitroquinoline (96 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80-100% ethyl acetate/hexanes eluent) to give 90 mg (55%) of the title compound as a solid. mp 199°-200°. FDMS: m/e=433. α[D]589 =+76.80 (c=0.42, chloroform).
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22].[Cl-].[NH4+]>O1CCOCC1>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[C:3]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])#[N:22]
Reactant: C=CCOC(=O)CC(=O)OCC=C
Reactant: N#CCCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: C=CCOC(=O)C(CCCCC#N)C(=O)OCC=C
Temperature: 40 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
21.71 g (542.9 mmol; 60% pure) of sodium hydride are added in portions to a solution of 100 g (542.9 mmol) of diallyl malonate in 700 ml of dry dioxane at 0° C. After gas evolution ceases, the reaction mixture is warmed to 40° C. and stirred for 1 hour. Then 43.98 g (271.5 mmol) of 5-bromovaleronitrile in 350 ml of dry dioxane are added dropwise, and the mixture is stirred at 110° C. for 12 hours. After the reaction is complete, the mixture is cooled to room temperature, mixed with 400 ml of saturated ammonium chloride solution and extracted with ethyl acetate. After phase separation, the aqueous phase is back-extracted three times with 250 ml of ethyl acetate each time. After the organic phases have been combined they are washed with saturated sodium chloride solution and dried over sodium sulfate, and then the solvent is stripped off in vacuo. Excess diallyl malonate is subsequently removed by high vacuum distillation (boiling point: 57° C.; 0.074 mbar). The distillation residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). 105 g (233 mmol, approx. 60% purity, 43% yield) of a liquid are obtained. This product is reacted without further purification in the subsequent stage. A small amount is purified by preparative HPLC for analytical characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:29]([C:20]1[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=1)(=[O:31])=[O:30])[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc4ccccc4c3)c3c(F)cc(F)cc23)CC1

Procedure:
(5.1 mg, 29%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and 2-naphthalenesulfonyl chloride (13.6 mg, 0.06 mmol) with 1M NaN(TMS)2 (60 μL, 0.06 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3Cl)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccccc4Cl)nc3n2)cc1
Temperature: 4 °C
Yield: 64.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (16.4 g), N,N'-carbonyldiimidazole (17.5 g) and 2-amino-7-(2-chlorophenoxy)-1,8-naphthyridine (18.5 g). The product produced by precipitation in water (28 g; m.p. approximately 80° C.) is dissolved in boiling ethanol (800 cc). After 15 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×20 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-[7-(2-chlorophenoxy)-1.8-naphthyridin-2-yl]-4-methoxybenzamide (17.8 g) is produced, m.p 190° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=[N:39][N:38]([CH2:41][C:42]3[CH:47]=CC=CC=3Cl)[C:36]=2N=1)(C)(C)C.CN1C(C2CCCN2)=CC=N1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][CH:23]2[C:41]2[N:38]([CH3:36])[N:39]=[CH:47][CH:42]=2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cn1nccc1C1CCCN1
Product: Cn1nccc1C1CCCN1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-methyl-5-(pyrrolidin-2-yl)-1H-pyrazole. MS (m/e): 451.4
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]3[C:13]([O:15][C:16](=O)[C:9]=3[CH:8]=2)=[O:14])=[CH:5][C:4]2[C:18]([O:20][C:21](=O)[C:3]=2[CH:2]=1)=[O:19].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[OH:15][CH2:16][C:9]1[CH:8]=[C:7]([C:6]2[CH:1]=[CH:2][C:3]([CH2:21][OH:20])=[C:4]([CH2:18][OH:19])[CH:5]=2)[CH:12]=[CH:11][C:10]=1[CH2:13][OH:14]
Reactant: O=C1OC(=O)c2cc(-c3ccc4c(c3)C(=O)OC4=O)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: OCc1ccc(-c2ccc(CO)c(CO)c2)cc1CO

Procedure:
Compound 4 is prepared in two steps from commercially available 3,3′,4,4′-biphenyltetracarboxylic dianhydride as shown in Scheme 4. Dianhydride is reduced with lithium aluminium hydride in dioxane to give 3,3′,4,4′-tetra(hydroxymethyl)-1,1′-biphenyl 3, which is in turn oxidised following a standard swern oxidation procedure to afford tetracarbaldehyde 4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1cc(Br)ccc1NCC1CC1
Temperature: 96 °C
Reaction time: 15 h
Yield: 105 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (9.25 g, 42 mmol), cyclopropanemethylamine (4.49 g, 63.1 mmol) and N,N-diisopropylethylamine (13.5 g, 105 mmol) in ethanol (100 mL) is stirred at 96° C. for 15 h. After cooling to room temperature, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography (silica, eluent: ethyl acetate) to give 11.96 g of 4-bromo-N-(cyclopropylmethyl)-2-nitroaniline. Yield 100%, ES-MS: 271/273 [M+H].
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:10]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1.Cl.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29]>C(Cl)Cl>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28]([N:21]1[CH2:20][CH2:19][N:18]([C:10]2[C:9]([CH3:8])=[CH:14][C:13]([N+:15]([O-:17])=[O:16])=[CH:12][N:11]=2)[CH2:23][CH2:22]1)=[O:29]
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])cnc1N1CCN(C(=O)c2c(F)cccc2F)CC1
Reaction time: 8 h
Yield: 93 %

Procedure:
Add triethylamine drop wise (3 equiv) to a suspension of 1-(3-methyl-5-nitro-pyridin-2-yl)-piperazine; hydrochloride (6.91 g, 24.13 mmol) in DCM (120 mL). Add 2,6-difluorobenzoylchloride (1 equiv.) Stir the mixture at room temperature overnight. Add additional 2,6-difluorobenzoylchloride (1.6 mL) and triethylamine (1.5 equiv.) to run reaction to completion. Allow the reaction to stand overnight. Dilute with DCM and extract several times with water. Dry the organic layer over Na2S2O4, filter, and remove solvent under reduced pressure. Wash solid several times with hexane to obtain. 8.08 g of (2,6-difluoro-phenyl)-[4-(3-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone (93% yield). ES+(m/z): 363 [M+1]
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][CH2:8][Cl:9])[CH2:3][CH2:4][CH3:5].[N-:10]=[N+:11]=[N-:12].[Na+].[OH-].[Na+]>CN(C=O)C.CCOCC>[ClH:9].[CH2:2]([NH:6][CH2:7][CH2:8][N:10]=[N+:11]=[N-:12])[CH2:3][CH2:4][CH3:5]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCNCCN=[N+]=[N-]
Yield: 68.8 %

Procedure:
7.0 g of 2-butylamino-ethyl chloride hydrochloride (Org. Synth. IV 1963, 333) are stirred together with 7.9 g of sodium azide in 50 ml of DMF at 50°. After cooling, 82 ml of 1N sodium hydroxide solution are added dropwise. The mixture is taken up in 700 ml of ether, washed with water and, after drying the ether phase, treated with 25 ml of hydrochloric acid (5 molar in dioxane). After evaporating the ether phase, the residue is suspended in ether. The crystals are filtered and washed with ether. There are obtained 5 g of 2-butylamino-ethyl azide hydrochloride, Rf=0.14.
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([C:7]2[N:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([CH3:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)CCC(=O)C1CCCCC1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)ccc1C1CCCCC1
Temperature: 55 °C
Reaction time: 14 h
Yield: 80.4 %

Procedure:
To a solution of 1-cyclohexylpentane-1,4-dione (1.32 g, 7.24 mmol) in dichloromethane (10 mL) was added ethyl 2-aminoacetate hydrochloride (1.01 g, 7.24 mmol) and solid sodium bicarbonate (1.52 g, 18.1 mmol). The reaction was heated at 55° C. for 6 hours, then stirred at 40° C. for an additional 14 hours, after which the reaction was nearly complete by LCMS analysis. The reaction mixture was cooled to room temperature, extracted with dichloromethane (3×50 mL), dried (sodium sulfate), filtered, and concentrated to a brown residue. Purification by silica gel column chromatography (Luknova 80 g, 20 mL/min) using 0 to 35% ethyl acetate in hexanes over 50 minutes afforded the product as a clear, colorless oil (1.45 g, 5.82 mmol, 80% yield). 1H NMR (400 MHz, CDCl3): δ (ppm) 5.86 (dd, 1H), 5.83 (d, 1H), 4.53 (s, 2H), 4.24 (q, 2H), 2.33 (m, 1H), 2.17 (d, 3H), 1.71-1.89 (m, 5H), 1.32-1.42 (m, 5H), 1.29 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[O:33][C:32]=2[CH:31]=[CH:30][C:29]=1[C:41]1[CH:42]=[CH:43][C:44]2[NH:45][C:46]3[C:51]([C:52]=2[CH:53]=1)=[CH:50][CH:49]=[CH:48][CH:47]=3.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CCCCCC.C1(C)C=CC=CC=1>[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[O:33][C:32]=2[CH:31]=[CH:30][C:29]=1[C:41]1[CH:42]=[CH:43][C:44]2[N:45]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[C:21]5[C:16]([C:15]([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)=[C:14]6[C:9]=4[CH:10]=[CH:11][CH:12]=[CH:13]6)=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:6][CH:7]=3)[C:46]3[C:51]([C:52]=2[CH:53]=1)=[CH:50][CH:49]=[CH:48][CH:47]=3
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Reactant: c1ccc2c(c1)[nH]c1ccc(-c3ccc4oc5ccccc5c4c3)cc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: c1ccc(-c2c3ccccc3c(-c3ccc(-n4c5ccccc5c5cc(-c6ccc7oc8ccccc8c7c6)ccc54)cc3)c3ccccc23)cc1
Yield: 81.4 %

Procedure:
Into a 200-mL three-neck flask were put 1.0 g (2.6 mmol) of 9-(4-bromophenyl)-10-phenylanthracene, 0.86 g (2.6 mmol) of 3-(dibenzofuran-2-yl)-9H-carbazole, and 0.50 g (5.2 mmol) of sodium tert-butoxide. The air in the flask was replaced with nitrogen, and then, to the mixture were added 50 mL of toluene and 0.20 mL of tri(tert-butyl)phosphine (a 10 wt % hexane solution). This mixture was degassed under reduced pressure while being stirred, and then 75 mg (0.13 mmol) of bis(dibenzylideneacetone)palladium(0) was added to this mixture. This mixture was stirred at 110° C. for 2 hours under a nitrogen stream. After the stirring, this mixture was subjected to suction filtration through Celite, alumina, and Florisil. The obtained filtrate was concentrated to give a light-yellow oily substance. This oily substance was recrystallized from toluene/hexane to give 1.4 g of light-yellow powder in 80% yield. The synthesis scheme of Step 4 is shown in (a-4).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][CH2:11][S:12][C:13]([F:16])([F:15])[F:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.N#N>[C:36]1([NH:35][C:17]([C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][CH2:11][S:12][C:13]([F:14])([F:15])[F:16])=[O:19])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCSC(F)(F)F)C(=O)O
Reactant: Nc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CCSC(F)(F)F)C(=O)Nc1ccccc1
Yield: 67.6 %

Procedure:
N-Boc-trifluoromethionine (200 mg, 0.659 mmol) was dissolved in 6.6 ml of dry THF in the presence of N2, and the temperature was adjusted to −78° C. Subsequently, N-methylmorpholine (0.09 ml, 0.794 mmol) was added thereto, and the mixture was stirred. Two minutes later, isobutyl chloroformate (0.10 ml, 0.794 mmol) was added thereto, and the mixture was stirred for 2 minutes. Finally, aniline (0.07 ml, 0.794 mmol) was added thereto. TLC was performed to confirm disappearance of the starting compound, and the solid matters were filtered, followed by distillation of THF under reduced pressure. The residue was purified by column chromatography (hexane/ethyl acetate=80/20 then 70/30), thereby the product (168.6 mg, 65%) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: BrCCCCCCOCCc1ccccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-pyridineethanol (5 g), 1,6-dibromohexane (20 ml), 50% (w/v) sodium hydroxide (20 ml) and tetra-n-butylammonium hydrogen sulphate (500 mg) was stirred at room temperature for 6 h, Water (100 ml) was added and the mixture was extracted with ether (2×100 ml). The organic extracts were washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with hexane→hexane-ether(1:1) to give the title compound as a colourless oil (6.6 g), t.l.c. (hexane-ether 1:1) Rf 0.19.
Reaction SMILES: CNCCN(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].CC1[N:19]=[C:18]([CH:20]=[O:21])[CH:17]=[CH:16]C=1.C([N-]C(C)C)(C)C.[Li+].CI>C1COCC1.O>[CH2:11]([C:10]1[N:19]=[C:18]([CH:20]=[O:21])[CH:17]=[CH:16][CH:9]=1)[CH3:12]
Reactant: [Li]CCCC
Reactant: Cc1cccc(C=O)n1
Agent: CC(C)[N-]C(C)C
Agent: CNCCN(C)C
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CCc1cccc(C=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
To a solution of N,N,N-trimethylethylenediamine (4.29 mL, 33 mmol) in THF (20 mL) at -25° C. was added n-BuLi (13.2 mL, 2.5M in hexanes, 33 mmol). This solution was stirred 15 minutes, then transferred into a -78° C. solution of 6-methyl-2-pyridine-carboxaldehyde (3.63 g, 30 mmol) in THF (80 mL). After stirring 30 minutes at -78° C., a THF (50 mL) solution of lithium diisopropylamide (33 mmol) was added and the now dark red mixture was stirred 1 hour at -78° C. Methyl iodide (5.68 g, 40 mmol) in THF (10 mL) was added and reaction mixture was allowed to warm to r.t. for 4 hours. Water and 25% aq. NH4OAc were added, the crude product was extracted with EtOAc (2×) and solvents were evaporated. Purification by flash chromatography (from 5% to 10% EtOAc in hexanes) gave 660 mg of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][O:6][C:7]1[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=[C:9]([CH3:21])[CH:8]=1)[CH3:2].[O:24]1CCOCC1>O>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=[C:9]([CH:21]=[O:24])[CH:8]=1)[CH3:23]
Reactant: C1COCCO1
Reactant: CCN(CC)CCOc1cc(C)nc2c1ccc1cccnc12
Solvent: O
Product: CCN(CC)CCOc1cc(C=O)nc2c1ccc1cccnc12
Yield: 19 %

Procedure:
A solution of SeO2 (0.83 g, 7.5 mmol) in a mixture of dioxane (38 mL) and water (3 mL) was heated to reflux in a two-neck 100 mL round-bottomed flask. A solution of diethyl-[2-(2-methyl-[1,10]phenanthrolin-4-yloxy)-ethyl]amine (0.93 g, 3.0 mmol) in hot dioxane (20 mL) was added through an addition funnel over a period of 15 minutes and the reaction mixture was refluxed for 45 minutes. The solvent was evaporated in vacuo and the residue was treated with methylene chloride (100 mL) and saturated NaHCO3 (100 mL). The aqueous layer was extracted with methylene chloride (3×100 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (SiO2, MeOH/DCM, 1:40) to afford the pure material as a brown solid (0.19 g, 19%).
Reaction SMILES: [C:1]12[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.Br[CH2:22][CH2:23][F:24].CCN(C(C)C)C(C)C>CC#N>[F:24][CH2:23][CH2:22][NH:20][CH:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[C:1]3[C:2]4[CH2:3][CH2:4][CH2:5][C:6]=4[S:7][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1
Reactant: NC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reactant: FCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FCCNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 82.5 %

Procedure:
Reference: For the preparation of the starting material compound 1, see Example 147. Into a 100-mL round-bottom flask, a solution of 1-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (250 mg, 0.87 mmol, 1.00 equiv) in CH3CN (15 mL) was added 1-bromo-2-fluoroethane (220 mg, 1.73 mmol, 2.00 equiv) and DIPEA (200 mg, 1.74 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred for 7 h at 70° C. in an oil bath. After completion, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to give 240 mg (83%) of the desired 1-N-(2-fluoroethyl)-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine as a light yellow solid. MS (ES, m/z): 334 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].Cl.[H-].[Na+].Cl[C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[O:28])=[CH:25][C:24]=2[O:39][CH3:40])[N:13]=1>O1CCOCC1.O>[NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:16]1[C:17]([C:18]([F:19])([F:21])[F:20])=[CH:12][N:13]=[C:14]([NH:22][C:23]2[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]3[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]3)=[O:28])=[CH:25][C:24]=2[O:39][CH3:40])[N:15]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(O[C@@H]2CCC[C@H]2N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R,R)-2-aminocyclopentanol×HCl (155 mg) is added to a suspension of NaH (135.2 mg) in dioxane (0.75 mL) and stirred for 30 min at RT. Then 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (250 mg) is added. After 18 h, H2O (50 mL) is added. The precipitate formed is filtered off, washed with H2O, dissolved in CH2Cl2 and extracted with aqueous KHSO4 solution (10%). The aqueous phase is made basic again with K2CO3 and extracted with CH2Cl2. The organic phase is dried on magnesium sulphate, filtered to remove the desiccant and the solvent is eliminated in vacuo.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][O:7][CH2:8][CH:9]([NH:19][C:20](=[O:34])[CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])C.[OH-].[Na+]>CO>[CH2:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][CH:9]([CH2:10][O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:8][O:7][CH2:6][CH2:5][C:4]([OH:35])=[O:3])=[O:34])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CCOCC(COCCC(=O)OCC)NC(=O)CCNC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCOCC(COCCC(=O)O)NC(=O)CCNC(=O)OCc1ccccc1

Procedure:
The compound 8 was prepared using General Procedure A with diester 29 (1.32 g, 2.66 mmol) and an aqueous NaOH solution (0.85 g, 21.29 mmol in 10 mL of H2O) in methanol (10 mL). The desired diacid (8) was obtained in 96% (1.12 g) yield as a colorless syrup. 1H NMR (CDCl3): δ 7.32 (m, 5H, ArH), 6.59 (s, 1H, NH), 5.54 (s, 1H, NH), 5.08 (s, 2H, OCH2Ar), 4.18 (m, 1H, CH), 3.69 (m, 4H, CH2O), 3.56 (m, 2H, CH2O), 3.45 (m, 4H, CH2NHCO and CH2O), 2.55 (m, 4H, CH2O), 2.43 (m, 2H, CH2CO); ESI-MS m/z 475[M+Cl]−; 463[M+Na]+, 441 [M+H]+, 439[M−H]−.