Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:20][C:2]1([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[O:23][CH2:22][CH2:21][O:1]1
Reactant: CC(=O)CCCCCCN1C(=O)c2ccccc2C1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(CCCCCCN2C(=O)c3ccccc3C2=O)OCCO1

Procedure:
A mixture of 142.0 g (0.52 mole) of N-(7-oxooctyl)phthalimide, 60 ml of ethylene glycol, 5.80 g of p-toluenesulfonic acid and 290 ml of benzene was refluxed overnight using a Dean-Stark trap to collect the azeotrope. The reaction was cooled, treated with 2 N NaOH solution, the organic layer separated, dried over anhydrous potassium carbonate, filtered and stripped to give 125.25 g of orange oil, 76% pure by gc (SE-30, 90°-280°@16°/min).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:13][C:14](=[O:29])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[CH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N+](C1C=C[C:47]([O:50]C(=O)OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.[CH2:63]([N:65]([CH2:68][CH2:69][NH2:70])[CH2:66][CH3:67])[CH3:64]>C1COCC1>[CH2:63]([N:65]([CH2:66][CH3:67])[CH2:68][CH2:69][NH:70][C:47]([N:13]1[C:14](=[O:29])[C:15]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[C:12]1=[O:30])=[O:50])[CH3:64]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Reactant: CCN(CC)CCN
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)N1C(=O)C(c2cn(C)c3ccccc23)=C(c2cn(C)c3cc([N+](=O)[O-])ccc23)C1=O
Reaction time: 0.25 h
Yield: 10.3 %

Procedure:
To a cold solution of 3-(1-Methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dione (200 mg, 0.5 mmol) (see Davis U.S. Pat. No. 5,057,614) in THF (7 mL) was added dropwise, lithium bis(trimethylsilyl)amide (0.55 mmol, 0.55 mL, 1 M in THF). The resulting red suspension was stirred for 15 min. Bis(p-nitrophenyl)carbonate (213 mg, 0.7 mmol) was added. The solution was stirred at 0° C. for 0.5 h. Diethylaminoethylamine (69.7 mg, 0.6 mmol) in THF (2 mL) was added, and stirring was continued for 2 h. The solvent was evaporated and the residue was purified by flash chromatography to give 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrole-1-carboxylic acid (2-diethylamino-ethyl)-amide (28 mg, 10%).
Reaction SMILES: B.O1CCCC1.[Br:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=[CH:16][C:10]=2[C:9]=1[CH3:20].B.CO>O1CCCC1>[Br:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=[CH:16][C:10]=2[C:9]=1[CH3:20]
Reactant: Cc1c(Br)sc2cc(C(=O)O)ccc12
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Br)sc2cc(CO)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
A solution of borane-tetrahydrofuran complex (150 ml. of 1M solution in THF) was added dropwise with stirring to a solution of 2-bromo-3-methylbenzo[b]thiophene-6-carboxylic acid (7.32 g.) in dry tetrahydrofuran (120 ml.) at 0° C. under an atmosphere of dry nitrogen. The solution was stirred at room temperature for 4 hours and then the excess borane was decomposed by the cautious addition of methanol. The solution was evaporated and the residue was dissolved in ether. The solution was washed with water, dried (Na2SO4) and evaporated to give a solid which was crystallized from ether/petrol (b.p. 40°-60°) to give 2-bromo-6-hydroxymethyl-3-methylbenzo[b]thiophene (5.70 g.), m.p. 91° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC.[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br>C(#N)C.C(Cl)Cl>[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[C:7](=[O:12])[C:8]1=[O:11]
Reactant: Clc1ccccc1CBr
Reactant: Cc1cccc2c1NC(=O)C2=O
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cccc2c1N(Cc1ccccc1Cl)C(=O)C2=O
Reaction time: 60 h
Yield: 88.2 %

Procedure:
Combine 7-methylisatin (80 mg, 0.5 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene beads(630-720 mg, 1.4-1.6 mmol, 2.2 mmol/g, Fluka) and 2-chlorobenzyl bromide (0.065 mL, 0.5 mmol) in acetonitrile (5 mL) in a 20 dram scintillation vial and shake on a rotator for 2.5 days at room temperature. Dilute with CH2Cl2 or acetonitrile and filter off beads. Concentrate in vacuo to obtain 126 mg (88%) of the title compound as crude product as a red-orange solid. MS (ES): m/z=286 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]=[C:26]([N:23]4[CH2:24][CH2:25][CH:21]([N:20]([CH3:36])[CH3:19])[CH2:22]4)[S:27][C:28]=3[CH:34]=2)=[O:9])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4cccc(Cl)c4)cc3s2)C1
Yield: 49.2 %

Procedure:
Combine 3-chlorocinnamic acid (0.104 g, 0.572 mmol), CH2Cl2 (13 mL), and DMF (3 drops) with stirring. Add oxalyl chloride (0.17 mL, 1.91 mmol) and stir the mixture for 2.5 h at room temperature. Concentrate the mixture in vacuo, add hexane (approximately 10 mL), re-concentrate in vacuo, and add CH2Cl2 (4.0 mL). Transfer the mixture to a 40 mL reaction vial and add a mixture of 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.100 g, 0.381 mmol) (Example 1, step 3) in CH2Cl2 (5.0 mL). Shake the reaction vial for 1 h at room temperature. Dilute the reaction mixture with CH2Cl2 (25 mL), wash with 1.0 M NaOH (aqueous) (4×25 mL), dry over sodium sulfate, filter, and concentrate in vacuo. Purify the residue using silica gel chromatography (12 g column, 10-20% MeOH(CH2Cl2) to afford the title compound as a yellow solid (80 mg, 49%). mass spectrum (m/e): 427.2 [M+1], 425.2 [M−1]. 1H NMR (400 MHz, CDCl3 (spiked with CD3OD)): δ 8.28 (s, 1H), 7.61 (d, 1H, J=15.6 Hz), 7.47-7.43 (m, 2H), 7.32 (d, 1H, J=7.2 Hz), 7.30-7.23 (m, 2H), 7.19 (dd, 1H, J=8.8, 2.0 Hz), 6.57 (d, 1H, J=15.6 Hz), 3.78 (t, 1H, J=8.8 Hz), 3.68 (t, 1H, J=10.0 Hz), 3.50 (m, 1H), 3.36 (t, 1H, J=9.2 Hz), 2.88 (m, 1H), 2.29 (s, 6H), 2.23 (m, 1H), 1.97 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([CH3:11])([CH3:10])[CH2:5][CH2:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.C(=O)=O.Cl.[CH3:23][O:24][NH:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:23][O:24][N:25]([CH3:26])[C:7](=[O:9])[CH2:6][CH2:5][C:4]([CH3:11])([CH3:10])[C:3]([O:2][CH3:1])=[O:12]
Reactant: CNOC
Reactant: COC(=O)C(C)(C)CCC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CCC(=O)N(C)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methoxy-4,4-dimethyl-5-oxopentanoic acid from Step B (7.00 g, 40.2 mmol), in DCM, was added DMF (0.1 mL), followed by the slow addition of oxalyl chloride (5.00 g, 39.4 mmol) over 33 minutes, during which time the reaction flask was maintained under a constant stream of dry nitrogen. Stirring was continued under a light stream of dry nitrogen for an additional hour, during which time the rate of carbon dioxide evolution diminished. This freshly formed acid chloride was then transferred via canula into a 500 mL round bottom flask, cooled to 0° C., which already contained N-methoxymethanamine hydrochloride (5.76 g, 59.1 mmol) and triethylamine (15.9 g, 158 mmol). Fifteen minutes after complete addition of the acid chloride, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After 1 h at ambient temperature, diethyl ether (100 mL) was added to precipitate some of the triethylamine hydrochloride, which was filtered and washed with more diethyl ether. The combined organics were then washed with 1M HCl (100 mL×2), 1M NaOH (100 mL), water (100 mL), half-saturated brine (100 mL) and saturated brine (100 mL). The organics were then dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound which was used without further purification. MS: m/z=218 (M+1).
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:6]1([CH3:15])[C:10](=[O:11])[CH2:9][C:8]([CH2:13][CH3:14])([CH3:12])[O:7]1)[CH3:5].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[C:19]([CH2:25][CH3:26])[CH:18]=1.Cl>C(COC)OC>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:9]2[C:8]([CH2:13][CH3:14])([CH3:12])[O:7][C:6]([CH2:4][CH3:5])([CH3:15])[C:10]2=[O:11])=[C:19]([CH2:25][CH3:26])[CH:18]=1
Reactant: CCc1cc(Br)ccc1C=O
Reactant: CCC1(C)CC(=O)C(C)(CC)O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: CCc1cc(Br)ccc1C=C1C(=O)C(C)(CC)OC1(C)CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 110.8 %

Procedure:
Sodium methoxide (5.08 g, 0.094 mol) is added to a solution of 2,5-diethyl-2,5-dimethyldihydrofuran-3-one (8 g, 0.047 mol) in dimethoxyethane (40 ml) at 0° C. The reaction mixture is stirred for 15 minutes at 0° C. and a solution of 4-bromo-2-ethyl benzaldehyde (8.96 g, 0.042 mol) in dimethoxyethane (8 ml) is added. The reaction mixture is stirred at 0° C. for 1 hour, acidified to pH 1 with 2N aqueous hydrochloric acid and extracted with diethyl ether (3×75 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure to give 4-[1-(4-bromo-2-ethylphenyl)methylidene]-2,5-diethyl-2,5-dimethyldihydrofuran-3-one (17 g), used without further purification in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18].C(OC(NC1C=CC(CC(O)=O)=CC=1)=O)(C)(C)C>>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:31]([C:29]2[O:30][C:26]([C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=3)=[CH:27][CH:28]=2)=[O:32])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Product: CC(C)(C)c1cc(NC(=O)c2ccc(-c3ccc([N+](=O)[O-])cc3)o2)cc(C(C)(C)C)c1O
Yield: 56 %

Procedure:
The experimental protocol used is the same as that described for intermediate 40.1, 2,6-di-t-butyl-4-aminophenol and 5-(4-nitrophenyl)-2-furan carboxylic acid replacing thiazolidine and 4-(t-butoxycarbonylamino)-benzeneacetic acid respectively. The expected compound is obtained in the form of a colourless oil with a yield of 56%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:3].[Br:16]C[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23].[C:24](OC)(C)(C)C>>[Br-:16].[Cl:23][CH:22]([CH2:21][CH2:20][CH2:19][CH3:18])[CH2:3][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:24])[CH3:1]
Reactant: COC(C)(C)C
Reactant: CCCCCCCCCCCCN(C)C
Reactant: ClCCCCCCBr
Product: CCCCCCCCCCCC[N+](C)(C)CC(Cl)CCCC
Product: [Br-]
Temperature: 58 °C

Procedure:
To a 500 mL, round-bottomed flask equipped with air condensers and magnetic stirring was charged N,N-dimethyldodecylamine (95.13 grams, 0.513 moles), 1-bromo-6-chlorohexane (102.40 grams, 0.513 moles) and tert-butylmethylether (200 mL). The reaction was maintained at 58° C. for 14 hours. During this time a white precipitate formed. The reaction was cooled to room temperature and tert-butylmethylether (350 mL) was added. Solids were collected by vacuum filtration. The mother liquor was allowed to react further at 60° C. and solids were collected in a similar fashion. The combined solids were dried in a vacuum oven at 35° C. for 24 hours, yielding 127.36 grams.
Reaction SMILES: [CH2:1]([C:5]1([CH2:34][CH2:35][CH2:36][CH3:37])[C:17]2[CH:16]=[C:15]([C:18]3[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[C:38]([CH2:40][C:41]([OH:43])=[O:42])#[N:39]>C(#N)C.N1CCCCC1>[C:38]([C:40](=[CH:23][C:21]1[S:22][C:18]([C:15]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:9][CH:10]=4)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:34][CH2:35][CH2:36][CH3:37])[C:17]=3[CH:16]=2)=[CH:19][CH:20]=1)[C:41]([OH:43])=[O:42])#[N:39]
Reactant: CCCCN(CCCC)c1ccc2c(c1)C(CCCC)(CCCC)c1cc(-c3ccc(C=O)s3)ccc1-2
Reactant: N#CCC(=O)O
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCN(CCCC)c1ccc2c(c1)C(CCCC)(CCCC)c1cc(-c3ccc(C=C(C#N)C(=O)O)s3)ccc1-2

Procedure:
As shown in Scheme 2, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21). Then, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a). Finally, in acetonitrile, 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 2-Cyano-3-[5-(9,9-dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophen-2-yl]-acrylic acid (23a).
Reaction SMILES: [C:1]([C:3]1([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)#[CH:2].C#CCCCCCC.[Br:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:14]([O:13][C:12](=[O:18])[NH:11][C:3]1([C:1]#[C:2][C:31]2[CH:32]=[CH:33][C:28]([Br:27])=[CH:29][CH:30]=2)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Brc1ccc(I)cc1
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(Br)cc2)COC(C)(C)OC1
Yield: 63 %

Procedure:
When tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and 4-bromo-iodobenzene was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 63% yield, as a pale paste, which solidified on standing. 1H-NMR (CDCl3) 1.43 (s, 2H); 1.46 (s, 9H); 1.48 (s, 3H); 4.00 (d, 2H, J=11.35 Hz); 4.08 (d, 2H, J=11.41 Hz); 5.19 (s, 1H); 7.26 (d, 2H, J=6.74 Hz); 7.41 (d, 2H, J=6.67 Hz).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=3)[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A solution of Compound 35 (3 g, 16.57 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 729 mg, 18.22 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (2.28 mL, 18.23 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 3.23 g (67%) of white solids. M.P. 107° C. 1H NMR (DMSO-d6): δ 5.27 (s, 2H), 7.19 (m, 2H), 7.29 (dd, J=3.9, 9.0 Hz, 1H), 7.47 (m, 2H), 7.65 (td, J=5.5, 9.0 Hz, 1H), 7.81 (dd, J=2.9, 7.9 Hz, 1H). Anal. (C15H9F2NO3) C, H, N.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.CNC1CCCCC1NC>CCOC(C)=O.O.C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: COC(=O)c1ccc2c(F)c[nH]c2c1
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(F)cn(-c3ccc(F)cc3)c2c1
Temperature: 95 °C

Procedure:
Compound 69a (0.264 mmol, 51 mg), Cut (0.0264 mmol, 5 mg) and K3PO4 (0.66 mmol, 40 mg) were combined in a sealed reaction tube and the vial was back-flushed with N2. 4-fluoro-iodobenzene 69b (0.264 mmol, 0.0394 mL) and N,N′-dimethylcyclohexane-1,2-diamine (0.0792 mmol, 0.0125 mL) were added via syringe, followed by toluene. The reaction mixture was heated at 95° C. for 6 h. The reaction was diluted with EtOAc and water. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to give compound 69c.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
179 a) A suspension of 1-(3-nitro-phenyl)-piperazine hydrochloride (1.0 g, 4.1 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in acetonitrile (10 mL) at room temperature was added di-tert-butyldicarbonate (1.0 g, 4.6 mmol) and was stirred at room temperature for 3 days. The mixture was poured into water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (50 mL) and saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. 4-(3-Nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester was isolated as a yellow solid (1.169 g, 93%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 7.19 (dd, J=8.2, 1.7 Hz, 1H), 3.63-3.58 (m, 4H), 3.27-3.21 (m, 4H), 1.49 (s, 9H). MS=330 (M+Na)+. 179 b) (3-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from 4-(3-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.17 g, 3.81 mmol) in a manner analogous to Example 111a. Product isolated as a yellow solid (0.993 g, 94%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.05 (t, J=7.7 Hz, 1H), 6.35 (d, J=8.8 Hz, 1H), 6.26-6.22 (m, 2H), 3.61 (br s, 2H), 3.57-3.53 (m, 4H), 3.12-3.07 (m, 4H), 1.48 (s, 9H). MS=278 (MH)+. 179 c) 4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 1.625 mmol) and 4-(3-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.803 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (90.0 mg, 0.165 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.70 g, 79%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.6 Hz, 1H), 8.24 (d, J=8.3 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.32 (s, 1H), 7.24 (t, J=8.1 Hz, 1H), 7.05-6.99 (m, 2H), 6.89 (s, 1H), 6.59 (d, J=8.2 Hz, 1H), 3.63-3.58 (m, 4H), 3.22-3.17 (m, 4H), 3.10 (s, 3H), 1.50 (s, 9H). MS=549 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[N:19]=[CH:18][N:17]=1>CN(C=O)C>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[N:19]=[CH:18][N:17]=[C:16]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH:21]=1
Reactant: COc1ccccc1-c1cc(Cl)ncn1
Reactant: CN(C)S(=O)(=O)Cc1cccc(N)c1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(Nc2cccc(CS(=O)(=O)N(C)C)c2)ncn1
Temperature: 80 °C

Procedure:
A mixture of (3-aminophenyl)-N,N-dimethylmethanesulfonamide (0.107 g, 0.50 mmol) and 4-chloro-6-(2-methoxyphenyl)-pyrimidine (0.110 g, 0.10 mmol) in DMFA (3 mL) was stirred at 80° C. till the reaction completion (TLC control), then concentrated in vacuo and the residue was recrystallized from isopropanol to give C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N,N-dimethyl-methanesulfonamide (Reference compound 1)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](O)[CH2:14][OH:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
The mixture of ethyl-4-oxocyclohexanecarboxylate (10 g, 58.75 mmol), ethylene glycol (4.97 ml, 88.13 mmol) and p-TsOH (cat.) in toluene (80 mL) was refluxed for 16 h in a flask equipped with Dean-Stark adapter. Upon reaction completion, the mixture was cooled to room temperature and solvent was removed under reduced pressure to provide compound D2-1 (9.6 g, crude) as brown oil. The crude product was used in the next step without purification. 1H NMR (CDCl3, 400 MHz): δ 4.15-4.09 (m, 2H), 3.95 (s, 4H), 2.36-2.03 (m, 1H), 1.97-1.91 (m, 2H), 1.85-1.75 (m, 4H), 1.66-1.52 (m, 2H), 1.26-1.27 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]2[CH2:9][C@H:4]([CH2:5][CH2:6][C@@H:7]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:3]1.[Li+].[OH-:18]>C1COCC1.O>[C:13]([O:12][C:10]([C@H:7]1[CH2:6][CH2:5][C@H:4]([OH:3])[CH2:9][C@@H:8]1[C:2]([OH:18])=[O:1])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H]2C[C@@H]1C(=O)O2
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](O)C[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
tert-Butyl (1S,2S,5S)-7-oxo-6-oxabicyclo(3,2,1)octane-2-carboxylate was dissolved in THF—H2O. At 0° C., LiOH (3 eq.) was added and the resulting mixture was stirred at 0° C. for 2 hours. TLC showed starting material was consumed. The mixture was then acidified to pH of about 2. The product was extracted with EtOAc (×3). The combined extracts were washed with brine (×1); dried over MgSO4. After filtration, the filtrate was concentrated to give (1S,2S,5S)-2-(tert-butoxycarbonyl)-5-hydroxycyclohexanecarboxylic acid (quantitative).