Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[N:23]1([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:26]1[CH2:25][CH2:24][N:23]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1)[CH:11]=[CH:10]2
Reactant: CCOC(=O)CN1CCNCC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: CCOC(=O)CN1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 64.2 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (200 mg) and 1-piperazineacetic acid, ethyl ester (310 mg) to afford the sub-title compound as a solid (180 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12]O)=[N:10][CH:11]=1.C(=O)(O)[O-].[Na+].[ClH:19]>C(Cl)Cl>[ClH:3].[Cl:19][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(F)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(CCl)nc1

Procedure:
Add thionyl chloride (320 μL, 4.30 mmol) slowly to a 0° C. solution of (5-fluoro-pyridin-2-yl)-methanol (420 mg, 3.31 mmol) in methylene chloride (15 mL). Stir the reaction at 0° C. for 3 h and quench with isopropyl alcohol. Dilute the reaction contents with methylene chloride (50 mL) and then saturated aqueous sodium bicarbonate (20 mL). Separate the organic phase, dry(magnesium sulfate), filter and concentrate in vacuo to give an oil. The oil is treated with hydrochloric acid (10 mL, 3 M solution in dioxane) at room temperature for 30 min. The resultant solid is collected by filtration and washed with a minimal amount of cold diethyl ether to give 200 mg (33%) as a yellow solid. MS (APCI): m/z 146 [C6H5ClFN+H]+; 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 7.56-7.37 (m, 2H), 4.67 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH:26]=[CH2:27].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.Cl>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH:26]=[CH2:27])=[O:11]
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO200687543, 2.27 g, 11.8 mmol) and Ethyl (3S,4R)-4-amino-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 18, 2.7 g, 11.8 mmol) in dichloromethane (180 mL) was added HOBt (1.85 g, 11.8 mM) and N-methylmorpholine (3.8 mL, 35.43 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (4.07 g, 21.3 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight, treated by the addition of 2 N HCl (120 mL) and the resulting layers were evaporated. The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica gel, 35% ethylacetate in pet ether) to afforded 3.5 g (73.6%) as brown solid. NMR (400 MHz, DMSO-d6): δ 1.24 (t, 3H), 1.62 (m, 2H), 2.16 (s, 3H), 2.97 (m, 2H), 3.53 (m, 2H), 3.97 (m, 4H), 4.15 (q, 2H), 4.21 (m, 1H), 5.13 (d, 1H), 5.23 (d, 1H), 5.87 (m, 1H), 7.10 (d, 1H), 12.10 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CI.[C:19](=O)([O-])[O-].[Na+].[Na+].CN(C)[CH:27]=[O:28]>>[CH3:19][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:28][CH3:27])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Solvent: CI
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)cc1

Procedure:
A solution of 4-(4′-hydroxyphenyl)benzoic acid (4.98 g), methyliodide (5 ml), and sodium carbonate (7.19 g) in N,N-dimethylformamide (50 ml) was stirred for 17 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine. After dried over magnesium sulfate, the solution was evaporated in vacuo. The residue was triturated with n-hexane to afford methyl 4-(4′-methoxyphenyl)benzoate (5.45 g).
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(CC)CC.N>C(#N)C.[Cu]I.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.O>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][CH:9]2[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[CH2:6][CH2:5][N:4]3[C:10]2=[N:11][CH:2]=[C:3]3[C:31]#[C:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:15]1
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCC(OC2c3ccccc3CCn3c(C#Cc4ccccc4)cnc32)CC1
Temperature: 80 °C

Procedure:
To a solution of compound 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (100 mg, 0.24 mmoles) in ACN (600 μL) in a screw-capped vial under argon are added CuI (9 mg, 0.048 mmole), Pd(PPh3)4 (28 mg, 24 μmoles), phenylacetylene (109 μL, 0.96 mmole) and NEt3 (600 μL). The reaction mixture is heated at 80° C. overnight. Water is added and pH adjusted to 9-10 with concentrated aqueous ammonia solution. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.2) to (95:5:0.5) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford 4-(1-methylpiperidin-4-yloxy)-2-phenylethynyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [CH2:1](S)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCCC[CH2:18][C:19]([C:23]([O:25]OC(C)(C)C)=[O:24])([CH2:21]C)[CH3:20]>C1(C)C=CC=CC=1>[C:23]([O:25][CH2:1][CH3:2])(=[O:24])[CH:19]=[CH2:21].[C:23]([O:25][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:24])[C:19]([CH3:20])=[CH2:18]
Reactant: CCCCCCCCCCCCS
Reactant: CCCCCC(C)(CC)C(=O)OOC(C)(C)C
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCCCCCCCCC
Product: C=CC(=O)OCC

Procedure:
350 g of toluene, 135 g of ethyl acrylate, and 15 g of n-decyl methacrylate were polymerized with stirring in a reaction flask at 50°-60° C. under argon with 0.3 g of dodecyl mercaptan as a regulator and 2 g of t-butyl perneodecanoate as initiator. After about 30 minutes of reaction, the mixture was precipitated in methanol and the polymer was dried under vacuum.
Reaction SMILES: C(O[C@@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=O)C.[C:35]1(C)[C:40]([SH:41])=[CH:39][CH:38]=[CH:37][CH:36]=1.B(F)(F)F.[CH3:47]COCC>C(Cl)Cl>[C:9]([O:8][C@H:7]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]([S:41][C:40]2[CH:35]=[CH:36][C:37]([CH3:47])=[CH:38][CH:39]=2)[C@@H:6]1[N:24]1[C:25](=[O:34])[C:26]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]2[C:28]1=[O:29])(=[O:11])[CH3:10]
Reactant: CCOCC
Reactant: Cc1ccccc1S
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(C)cc2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 83 %

Procedure:
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-galactopyranose (Nilsson, U. et al. Carbohydr. Res. 1990, 208, 260) (1.7 g, 3.56 mmol) in CH2Cl2 (20 mL) was treated with thiocresol (663 mg, 5.34 mmol) and BF3.Et2O (1.5 mL) by the procedure described in the preparation of 1. After workup, the crude product was crystallized from Et2O. to gave the title compound 11 (1.62 g, 83%): m.p. 141-142° C.; [α]D22 +45.4° (c, 0.5, CHCl3); 1H-NMR (400 MHz, CDCl3), δ 1.97 (s, 3H), 2.05 (s, 3H), 2.08 (s, 3H), 2.31 (s, 3H), 4.09-4.24 (m, 3H), 4.62 (t, 1H, J=10.8 Hz), 5.49 (d, 1H, J=3.2 Hz), 5.64 (d, 1H, J=10.8 Hz), 5.80 (dd, 1H, J=10.8, 3.2 Hz), 7.07 (d, 2H, J=8.1 Hz), 7.32 (d, 2H, J=8.1 Hz), 7.76-7.80 (m, 4H); 13C-NMR (400 MHz, CDCl3) δ 20.52, 20.69, 21.14, 50.11, 61.63, 66.85, 68.81, 74.48, 84.35, 123.65, 129.62, 133.21, 134.40, 162.01, 163.10, 167.16, 167.90, 171.22; HRMS for C27H27NO9SCs (M+Cs) calcd 674.0461, found 674.0435.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH3:11][C:12]1([CH3:34])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:14][C:13]1=2>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:11][C:12]1([CH3:34])[CH2:21][CH:20]=[C:19]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:18]2[CH:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:14][C:13]1=2
Reactant: c1ccsc1
Reactant: COC(=O)c1ccc2c(c1)C(OS(=O)(=O)C(F)(F)F)=CCC2(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(c1cccs1)=CCC2(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 329.0 mg (3.93 mmol) of thiophene in 2.0 mL THF at 0° C. was added 251.8 mg (3.93 mmol, 1.56 mL of 2.5 M solution in hexanes) of n-butyllithium. After stirring for 3 h at 0° C., a solution of 845.0 mg (6.28 mmol) of ZnCl2 in 5.0 mL THF was added and the resulting solution stirred for 30 minutes. This solution was added to a second flask containing 570.0 mg (1.57 mmol) of methyl 5,5-dimethyl-5,6-dihydro-8-(trifluoromethylsulfonyl)oxy-naphthalene-2-carboxylate (Compound E4) and 76.0 mg (0.063 mmol) of tetrakis(triphenyphosphine)palladium(0) in 4.0 mL, THF, and the resulting solution was heated to 50° C. for 3 h. Upon cooling to room temperature the reaction was quenched by the addition of saturated aqueous NH4Cl. Extraction with EtOAc was followed by washing of the combined organic layers with H2O and saturated aqueous NH4Cl, and drying over MgSO4. The dry solution was concentrated under reduced pressure and the title compound was isolated from the residue as a yellow oil by column chromatography (5-10% EtOAc/hexanes).
Reaction SMILES: C([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([OH:25])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)\[C:11]([F:14])([F:13])[F:12])C.O[Li].O.Cl>CCO.C1COCC1.O>[F:12][C:11]([F:13])([F:14])/[C:10](/[C:15]1[C:24]([OH:25])=[CH:23][C:22]2[C:21]([CH3:26])([CH3:27])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)=[CH:9]\[CH:8]=[CH:7]\[C:6](\[CH3:30])=[CH:5]\[C:4]([OH:31])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/c1cc2c(cc1O)C(C)(C)CCC2(C)C)C(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(/C=C/C=C(/c1cc2c(cc1O)C(C)(C)CCC2(C)C)C(F)(F)F)=C\C(=O)O
Temperature: 40 °C

Procedure:
To a solution of (2E,4E,6Z)-8,8,8-trifluoro-7-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-octa-2,4,6-trienoic acid ethyl ester (Intermediate 5, 100 mg, 0.23 mmol) in EtOH-THF-H2O (2 mL, 2 mL, 0.3 mL) was added LiOH.H2O 29 mg, 0.69 mmol). The mixture was heated to 40° C. for 4 h and was cooled to ambient temperature, acidified with 1M HCl and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (40% EtOAc-hexane) to give a 3:2 mixture of the title compound and its 13-Z isomer (91 mg). Further purification by HPLC (20% EtOAc-hexane) afforded the title compound as a white solid (39 mg, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[OH:33])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)([OH:33])[CH:34]2[CH2:35][CH2:36][N:37]([C:14](=[O:15])[CH2:13][N:10]3[CH2:11][CH2:12][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[C:9]3=[O:17])[CH2:38][CH2:39]2)=[CH:28][CH:27]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
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: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of the product of Example 58D (171 mg, 0.518 mmol), the product of Example 32A (157 mg, 0.518 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (197 mg, 0.518 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.361 mL, 2.07 mmol) in CH2Cl2 (5 mL) was stirred at ambient temperature for 36 hours. The reaction mixture was diluted by CH2Cl2, and the organic mixture was washed with 1 N aqueous HCl and saturated NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50% ethyl acetate/hexanes) to afford purified material that was taken up in a minimal amount of ether. Addition of hexanes caused formation of a solid that was collected by vacuum filtration and air-dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.59-7.47 (m, 4H), 7.40-7.29 (m, 4H), 7.18-7.04 (m, 8H), 5.48 (s, 1H), 4.41-4.29 (m, 1H), 4.19 (d, J=16.5, 1H), 4.09 (d, J=16.6, 1H), 3.86-3.75 (m, 1H), 3.38-3.30 (m, 2H), 3.05-2.89 (m, 1H), 2.85-2.63 (m, 3H), 2.63-2.51 (m, 1H), 1.40-1.17 (m, 4H); MS (DCI+) m/z 617 (M+H)+.
Reaction SMILES: O.[CH3:2][C:3]1([CH3:13])[CH2:8][CH2:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH2:4]1.[O-]Cl.[Na+]>[Na+].[Br-].CCOC(C)=O>[CH3:2][C:3]1([CH3:13])[CH2:8][CH2:7][C:6]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:5][CH2:4]1
Reactant: CC1(C)CC=C(CCCO)CC1
Agent: [Br-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CC=C(CCC=O)CC1
Reaction time: 1 h
Yield: 71.8 %

Procedure:
PIPO (CAS RN: 091993-31-6; 5.04 g, 0.017 mol), NaBr (0.60 g, 0.006 mol) and KHCO3 (6.40, 0.063 mol) were charged in a 2 1 reactor together with water (60 g), EtOAc (250 g) and 3-(4,4-dimethyl-cyclohex-1-enyl)-propan-1-ol (100.0 g, 0.573 mol, purity: 96.5%). The pot temperature was set to 25° C. and 13% w/w aqueous NaOCl (426.8 g, 0.745 mol) was introduced over 2 hours. Stirring was continued for 1 hour and then the aqueous phase separated. Then 300 g of a 2% w/w aqueous ascorbic acid was added, and the reaction mixture was stirred for 1 hour. The aqueous phase was separated and the organic phase washed with NaHCO3 and then with water. The organic phase thus obtained was concentrated and the crude product purified by a flash distillation (58°–60° C., 1 hPa) to yield 68.4 g of 3-(4,4-dimethyl-1-cyclohexen-1-yl)propanal (yield: 66%; GC purity: 92.3%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[N:14][NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])#[N:2].[H-].[Na+].[Br:30][CH2:31][CH2:32][C:33](Cl)=[O:34].[CH3:36][NH:37][CH3:38]>CCOCC>[BrH:30].[CH3:36][N:37]([CH:32]([CH3:31])[C:33]([N:13]([C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[N:14]=[N:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])=[O:34])[CH3:38]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Reactant: CNC
Reactant: O=C(Cl)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: Br
Product: CC(C(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N)N(C)C
Reaction time: 12 h

Procedure:
A solution of 10.0 g. (0.026 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene and 1.8 g. of sodium hydride in 750 ml. of ether is added to a solution of 4.45 g. (0.026 mol.) of 3-bromopropionyl chloride in 50 ml. of ether. The reaction mixture is stirred for 12 hours at 25°, then filtered to remove the precipitate formed during the reaction. The filtrate is cooled to -10° and dimethylamine (0.026 mol.) is added. The mixture is cooled for 12 hours, concentrated in vacuo and the residue is washed with ether-hexane and dried in vacuo to give 3-[2-(N,N-dimethylamino)propionyl]-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene hydrobromide.
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:6][C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[C:23](=[O:25])=[O:24].Cl>CN(C)C=O.CCOCC.O>[C:23]([C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][CH:13]=1)([OH:25])=[O:24]
Reactant: O=C=O
Reactant: COc1cccc(-c2cc(OC)ccc2Br)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cccc(-c2cc(OC)ccc2C(=O)O)c1
Temperature: -60 °C

Procedure:
12.1 g of 6-bromo-3,3'-dimethoxy-biphenyl was dissolved in 100 mL of dry dimethylformamide and the resulting solution was cooled to -60° C. under nitrogen. 55 mL of 1.7 M t-butyllithium in hexanes was added over a 20-minute period. The resulting solution was transferred to another flask containing a mixture of 275 mL of ether and dry ice which effected a lot of gas evolution. The mixture was allowed to warm to room temperature over a 3-hour period during which time a white precipitate had formed. The mixture was diluted with ether and treated with dilute hydrochloric acid and water. The organic layer was separated and the solvents were removed under reduced pressure to yield a yellow oil. Hexanes were added to the oil causing a solid to precipitate out. The solids were filtered and stirred in a 60:40% ether-hexane mixture to remove impurities. The solid was filtered and dried in vacuo to yield 7.82 g of 2-carboxy-5,5'-dimethoxybiphenyl as an off-white solid. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[F:16][C:17]([F:22])([F:21])[C:18](O)=O>>[Cl:13][C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2)=[C:2]2[NH:1][C:18]([C:17]([F:22])([F:21])[F:16])=[N:12][C:11]=12
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Product: Oc1nc2cc(Cl)c3nc(C(F)(F)F)[nH]c3c2nc1O
Temperature: 0 °C
Yield: 68 %

Procedure:
A mixture of 0,3 g (1,35 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 8 ml trifluoroacetic acid was refluxed for 3 h. After cooling to 0° C., the precipitated product was filtered off and washed with ice-cooled trifluoroacetic acid and ether to give 0,28 g (68%) 4-chloro-7,8-dihydroxy-2-trifluoromethyl-1H-imidazo(4,5-f)quinoxaline, m.p. >300° C. NMR (DMSO-d6): 7.10 (1H,s).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[CH2:28][N:14]3[C:15](=[O:27])[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@H:13]3[CH2:12]2)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].ClCCl>CO>[OH:10][C@@H:11]1[CH2:28][N:14]2[C:15](=[O:27])[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:19][C@H:13]2[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](O)C[C@@H]2C1
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
tert-Butyl (8S,9aR)-8-[(4-nitrobenzoyl)oxy]-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (156 mg, 0.372 mmol, 1.0 equivalent, Part E) was dissolved in methanol (3 mL). Potassium carbonate (20 mg, 0.145 mmol, 0.39 equivalent) was added and stirring was continued at room temperature for 30 minutes. The solvent was removed in vacuo, and the crude material was loaded onto a 12-g silica column with dichloromethane and eluted with 0-5% methanol:dichloromethane over 15 minutes, held at 5% methanol:dichloromethane for five minutes, then eluted with 10% methanol:dichloromethane for 10 minutes to afford the titled compound (65 mg, 0.240 mmol, 64.6% yield over two steps) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 4.44 (t, J=3.7 Hz, 1H), 4.39-3.86 (m, J=79.8 Hz, 2H), 4.06 (dt, J=17.5, 8.9 Hz, 1H), 3.83 (dd, J=13.2, 2.3 Hz, 1H), 3.51 (dd, J=13.2, 3.7 Hz, 1H), 3.35-2.96 (br s, 1H), 2.74-2.46 (m, 3H), 2.24 (dd, J=13.2, 6.0 Hz, 1H), 1.74 (ddd, J=12.0, 9.0, 3.0 Hz, 1H), 1.48 (s, 9H); MS (ESI+) m/z 270.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][C:28]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:29][C:16]2=3)=[CH:4][CH:3]=1.[CH2:34]([N:36](CC)CC)C.Br[CH:42](CBr)[C:43]#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:43][CH2:42][N:11]([CH2:12][CH2:13][CH:14]=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[N:25][C:20]=4[CH2:19][O:18][C:17]4[CH:26]=[CH:27][C:28]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:29][C:16]3=4)[CH2:10][CH:9]2[C:34]#[N:36])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCNCCNc1ccc(Cl)cc1)c1cccnc1CO2
Reactant: CCN(CC)CC
Reactant: N#CC(Br)CBr
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3)C(C#N)C1)c1cccnc1CO2
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(5-{3-[2-(4-chloro-phenylamino)-ethylamino]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl)-propan-2-ol (0.4 g, 0.87 mmol) in toluene (6 mL) was added triethylamine (0.48 mL, 3.44 mmol) and 2,3-dibromopropionitrile (0.19 mL, 1.72 mmol) and reaction mixture was heated to 110° C. (reflux) and stirred overnight for 18 h. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and extracted with 1.0N NaOH solution. The aqueous layer was back extracted twice with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated. The crude product was purified using a short plug of silica gel using ethyl acetate to give the desired product. 1H-NMR (CDCl3) δ: 1.05 (6H, s), 2.20–2.70 (8H, 2×m), 3.00 (1H, m), 3.10–3.40 (3H, 2×m), 4.50 (1H, br, s), 5.30 (2H, br, s), 6.20 (1H, t), 6.70–6.90 (3H, 2×d), 7.10–7.35 (4H, m), 7.50 (2H, d), 8.50 (1H, dd). ESI-MS m/z: 515 (M+1), UV retention time: 2.36 min.