Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S(Cl)(Cl)=O.[CH3:23]O>>[CH2:1]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:23])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCSCCCCCCCC(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCCCCCSCCCCCCCC(=O)OC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 8-heptylsulfanyl-octanoic acid (No. 6804237; 2.04 g, 7.43 mmol) was dissolved in methanol (20.4 mL), and the mixture was cooled to 0° C. While maintaining the temperature at 0° C., thionyl chloride (589.5 μL, 8.18 mmol) was added. The mixture was stirred at 0° C. for 5.0 minutes and at room temperature for 4.0 hours. The solvent was distilled off under reduced pressure. Methanol was then added to the residue, and the solvent was again distilled off under reduced pressure. This operation was repeated twice. To the residue was added dichloromethane. The organic layer was washed with water and a saturated brine in order, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The resulting residue was then purified with SP1 (SiO2 cartridge, 10% ethyl acetate/n-hexane, Rf=0.5) to obtain methyl 8-heptylsulfanyl-octanoate (No. 6804238; 2.29 g, quant.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[CH2:21][NH:22][O:23][CH:24]=[C:25]=[O:26])[CH2:14][CH2:13]1.[Cl:32][C:33]1[C:34](=[O:43])[NH:35][N:36]=[C:37]([O:40][CH2:41][CH3:42])[C:38]=1Cl.C(N(CC)CC)C.C(O)CC>O>[Cl:32][C:33]1[C:34](=[O:43])[NH:35][N:36]=[C:37]([O:40][CH2:41][CH3:42])[C:38]=1[N:22]([O:23][CH:24]=[C:25]=[O:26])[CH2:21][C:20]1[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:13][CH2:14]2)[CH:19]=1
Reactant: COc1ccc(CNOC=C=O)cc1N1CCN(Cc2ccc3ccccc3n2)CC1
Reactant: CCOc1n[nH]c(=O)c(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CCCO
Solvent: O
Product: CCOc1n[nH]c(=O)c(Cl)c1N(Cc1ccc(OC)c(N2CCN(Cc3ccc4ccccc4n3)CC2)c1)OC=C=O
Reaction time: 8 h
Yield: 53 %

Procedure:
A mixture comprising 2.4 g of 3-[4-(2-quinolylmethyl)-piperazin-1-yl]-carbonylmethoxy-4-methoxybenzylamine, 1 g of 4,5-dichloro-6-ethoxy-3(2H)-pyridazinone, 580 mg of triethylamine, 10 ml of propanol and 10 ml of water, was refluxed under heating with stirring overnight. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=6:1→chloroform:methanol=12:1) and then crystallized from diethyl ether to obtain 1.5 g of the above-identified compound as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:18]1=[O:35])[CH3:16].[H-].[Na+]>CN(C=O)C.CO>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:30][CH:29]=2)[C:18]1=[O:35])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C#N)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(C#N)cc21
Temperature: 180 °C
Yield: 12.6 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (45 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (61.5 mg) and NaH (9.0 mg) in DMF (1 mL) at room temperature. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (11 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1.N1C2C(=CC=CC=2)C=CC=1>>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[O:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:28][CH:29]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)C(C)Oc1ccc(Oc2c([N+](=O)[O-])cnc3ccccc23)cc1

Procedure:
Ethyl 2-[4-(3-nitroquinolin-4-yloxy)phenoxy]propionate (41) was prepared from 4-chloro-3-nitroquinoline and ethyl 2-(4-hydroxyphenoxy)propionate following essentially the same procedure as that described in Example 1. The compound was isolated as a yellow oil. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 9.3 (1H, s); 8.3-7.4 (4H, m, quinoline protons); 6.8 (4H, s, phenoxy protons); 4.7 (1H, q, CH--CH3); 4.2 (2H, q, OCH2 --CH3); 1.6 (3H, d, CH--CH3); 1.2 (3H, t, OCH2 --CH3).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:10]([CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccccc1Cl
Reactant: CNc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1N(C)c1ccccc1
Yield: 89.5 %

Procedure:
According to the general procedure B, 2-chlorotoluene (129 mg, 1.02 mmol) reacted with N-methylaniline (133 mg, 1.20 mmol) using 0.5 mol % Pd(OAc)2, 1 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (120 mg, 1.25 mmol) in toluene at 100° C. to give the title compound (180 mg, 89%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.37-7.21 (m, 6H), 6.78 (t, 1H, J=7.25 Hz), 6.61 (d, 2H, J=7.86 Hz), 3.30 (s, 3H), 2.22 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 149.08, 146.74, 136.80, 131.32, 128.93, 128.30, 127.46, 126.38, 116.72, 112.76, 39.00, 17.83. GC/MS(EI): m/z 197 (M+). Anal. Calcd for C14H15N: C, 85.24; H, 7.66; N, 7.10. Found: C, 85.09; H, 7.71; N, 7.24.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.C1(S[CH2:13][N:14]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:21][CH:22]=3)[S:15]2(=[O:17])=[O:16])C=CC=CC=1.CCCCCC>ClCCl>[Cl:4][CH2:13][N:14]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:21][CH:22]=2)[S:15]1(=[O:17])=[O:16]
Reactant: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(CSc1ccccc1)C2=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(CCl)C2=O
Reaction time: 3 h
Yield: 87 %

Procedure:
Sulfuryl chloride (0.34 g) was added dropwise with stirring to a solution of 2-phenylthiomethyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin (0.96 g) in dichloromethane. Stirring was continued at room temperature for three hours and the solution was stripped of volatiles. Dichloromethane was added and the solution was stripped again. Hexane was added to the residue and the mixture was stirred at room temperature overnight. The resulting white solid was collected and dried affording 2-chloromethyl-6-[2-(2-methoxyethoxy)-ethoxy]saccharin (0.69 g, 89% yield, mp 113°-115° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25]1[CH2:31][CH:30]2[NH:32][CH:27]([CH2:28][CH2:29]2)[CH:26]=1.C(O)(=O)C(O)=O>CCO>[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25]1[CH2:26][CH:27]2[N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:7]=3[CH:8]=[CH:9][NH:10]4)[CH:30]([CH2:29][CH2:28]2)[CH:31]=1
Reactant: C1=C(c2ccc3ccccc3c2)CC2CCC1N2
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: C1=C(c2ccc3ccccc3c2)CC2CCC1N2CCCOc1cccc2[nH]ccc12

Procedure:
The title compound is prepared according to the procedure of Example 2, Step 3, except that 4-(3-chloropropoxy)-1H-indole is used in place of 4-(2-chloro-ethoxy)-1H-indole and 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-ene is used in place of 3-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-1H-indole. The corresponding oxalate salt is prepared by treating the title compound with 1 equiv. of oxalic acid in EtOH. Yield: 35% of a white solid. mp: 118-123° C.; MS (ES) m/z: 409.3 (MH)+.
Reaction SMILES: CC(NC(C)C)C.C([Li])CCC.[CH3:13][CH:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15].[CH3:28][C:29]1([CH3:42])[C:39]2[C:40]3[C:35]([CH:36]=[CH:37][CH:38]=2)=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]1=[O:41]>O1CCCC1.O>[OH:41][C:30]1([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:19]=2[C:17]([N:16]([CH:25]([CH3:27])[CH3:26])[CH:14]([CH3:13])[CH3:15])=[O:18])[C:31]2=[C:40]3[C:35](=[CH:34][CH:33]=[CH:32]2)[CH:36]=[CH:37][CH:38]=[C:39]3[C:29]1([CH3:42])[CH3:28]
Reactant: CC1(C)C(=O)c2cccc3cccc1c23
Reactant: CC(C)N(C(=O)c1ccncc1)C(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)N(C(=O)c1ccncc1C1(O)c2cccc3cccc(c23)C1(C)C)C(C)C
Temperature: -80 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
Preparation of: ##STR30## To a cooled (-80° C.) and stirred solution of 5.25 g of N-(1-methylethyl)-2-propanamine in 500 ml of dry tetrahydrofuran there were added 20 ml of butyl lithium (2.5M in hexane) and, after stirring for 1 hour at -80° C., 10.3 g of N,N-bis(1-methylethyl)-4-pyridinecarboxamide (prepared as described in Tetr. Lett. 21, 4739, 1980). Stirring at -80° C. was continued for 3 hours and then there were added 9.3 g of 2,2-dimethylacenaphthylen-1(2H)-one. The whole was stirred for 18 hours at room temperature and was then poured into water. The product was extracted with ether and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 95:5). The eluent of the desired fraction was evaporated, yielding 4.2 g (20.9% ) of (±)-3-(1,2-dihydro-1-hydroxy-2,2-dimethyl-1-acenaphthylenyl)-N,N-bis(1-methylethyl)- 4-pyridinecarboxamide (comp. 5.006)
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:5](=[O:18])[C:4]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:3]1.[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:23][CH:20]([CH3:21])[C:19]([C:4]1[C:5](=[O:18])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)=[CH:7][N:2]([CH3:1])[CH:3]=1)=[O:22]
Reactant: CCC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)C(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A 2.7 g. portion of 1-methyl-3-propionyl-5-(3-trifluoromethylphenyl)-4(1H)-pyridinone was dissolved in 125 ml. of chloroform, and 2.3 g. of N-chlorosuccinimide was added. The mixture was stirred under reflux overnight, and was then cooled and washed, first with 1 N sodium hydroxide, and then with saturated sodium chloride solution. The organic layer was then dried over magnesium sulfate and evaporated under vacuum to obtain 2.2 g. of a partially crystalline solid. The product was crystallized from diisopropyl ether to obtain 1.2 g. of the desired product, m.p. 129°, dec., showing the following nmr peaks in DMSOd6 : δ7.5-8.4 (m, 6H, aromatic); 5.8-6.2 (q, 1H, CHCl); 1.5-1.6 (d, 3H, CHClCH3); 3.8 (s, 3H, N--CH3).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:40]=[CH:39][C:29]([O:30][CH2:31][CH2:32][NH:33][CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[C:28]([CH3:41])[CH:27]=3)=[N:22][CH:23]=2)=[CH:14][CH:13]=1>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:40]=[CH:39][C:29]([O:30][CH2:31][CH2:32][N:33]([CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:8][CH2:9][OH:10])=[C:28]([CH3:41])[CH:27]=3)=[N:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: OCCBr
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN(CCO)C1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
55 mg (0.40 mmol) of potassium carbonate and 28 μL (0.40 mmol) of 2-bromoethanol was added to a solution of 86.2 mg (0.20 mmol) of (2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopentylamine in 2 mL of DMF and the mixture was stirred for 24 hours at RT. Another 55 mg (0.40 mmol) of potassium carbonate and 28 μL (0.40 mmol) of 2-bromoethanol were added and the mixture was stirred for 8 hours at 50° C. The reaction mixture was evaporated down in vacuo and the residue was taken up in DCM. The organic phase was washed with water, dried over sodium sulfate, and evaporated down in vacuo. The crude product was purified by MPLC (silica gel, EtOAc/MeOH 95:5) and then MPLC (Alox, cyc/EtOAc 8:2) and triturated with DIPE. Yield: 2.9 mg (3% of theoretical); C29H31ClN2O2 (M=475.021); calc.: molpeak (M+H)+: 475/477 (Cl); found: molpeak (M+H)+: 475/477 (Cl); Rf value: 0.26 (silica gel, EtOAc/MeOH 95:5)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.Br[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].Cl>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.C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18]
Reactant: O=Cc1cccc(Br)c1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccccn2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 38.2 %

Procedure:
Ex-587A) To a THF solution (8 mL) of 2-bromopyridine (1.30 g, 8.23 mmol) at −78° C. was added 1.6 M n-BuLi in hexanes (5.3 mL, 8.48 mmol). The resulting dark red solution was stirred at −78° C. for 10 min, and a solution of 0.5 M ZnCI2 in THF (18 mL, 9.0 mmol) was added giving a light brown slurry. After warming to room temperature, 3-bromobenzaldehyde (0.816 mL, 7.0 mmol) and Pd(PPh3)4 (0.242 g, 0.21 mmol) were added, and the mixture was stirred for 18 h at room temperature under argon. The reaction mixture was poured into 1 N HCl (30 mL) and washed with diethyl ether. The aqueous layer was neutralized with NaHCO3 and extracted with diethyl ether. The solvent was removed in vacuo to give the crude product as an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0.49 g (38%) of the desired 3-(2-pyridinyl)benzaldehyde product as a colorless oil. GCMS: m/z=183 [M+].
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O.I[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1>CCOC(C)=O.O>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14]([C:39]3[CH:44]=[N:43][CH:42]=[CH:41][N:40]=3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:5]1
Reactant: Ic1cnccn1
Reactant: CC1CN(c2c(C=O)cc(B3OC(C)(C)C(C)(C)O3)c(F)c2F)CC(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC1CN(c2c(C=O)cc(-c3cnccn3)c(F)c2F)CC(C)O1
Temperature: 85 °C
Yield: 39.5 %

Procedure:
To a suspension of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (11.5 g, 29.1 mmol) and sodium carbonate (8.8 g, 83.1 mmol) in previously degassed acetonitrile/water (1/1) mixture (140 mL) was added iodopyrazine (5.7 g, 27.7 mmol) under nitrogen. Bis-(triphenylphosphine)-dichloro-palladium-(II) (758 mg, 1.08 mmol) was added at room temperature and the reaction was heated overnight at 85° C. The mixture was cooled to room temperature, diluted with EtOAc and water. The phases were separated and the aqueous phase was re-extracted with EtOAc (×2). The combined organic layers were dried over MgSO4 and concentrated to give a brown oil. Purification on silica gel (hexane/EtOAc 9/1, 8/2 then 7/3) yielded 3.65 g of an off-white solid. 1H-NMR (500 MHz, CDCl3) d 10.35 (s, 1H), 9.06 (t, 1H), 8.70 (dd, 1H), 8.57 (d, 1H) 8.32 (dd, 1H), 4.24 (m, 2H), 3.43 (dt, 2H), 3.05 (m, 2H), 1.32 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1I.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: Clc1ccc(I)c(Cl)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Product: O=[N+]([O-])c1cc(Br)ccc1-c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichloroiodobenzene and 2,5-dibromonitrobenzene were reacted under Ullmann conditions to give 4-bromo-2',4'-dichloro-2-nitrobiphenyl, m.p. 112°-115° C. This was reduced with stannous chloride to give 2-amino-4-bromo-2',4'-dichlorobiphenyl, b.p. 170°-175° C./0.2 mm. This was subjected to the Schiemann reaction using fluoroboric acid to give 4-bromo-2',4'-dichloro-2-fluorobiphenyl, m.p. 63°-65° C. This was reacted with cuprous cyanide in dimethyl formamide to give 2',4'-dichloro-4-cyano-2-fluorobiphenyl, m.p. 98°-103° C. which was then reacted with methylmagnesium iodide followed by hydrolysis with dilute hydrochloric acid to yield 4-acetyl-2',4'-dihloro-2-fluorobiphenyl, m.p. 65°-67° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f20) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[CH2:15][CH2:14]2)[CH:3]=1.Cl.[CH:31]12[CH2:37][CH:35]([O:36]1)[CH2:34][NH:33][CH2:32]2.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C(Cl)Cl.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:35]12[CH2:37][CH:31]([O:36]1)[CH2:32][N:33]([C:2]1[CH:11]=[C:10]3[C:5]([N:6]=[CH:7][CH:8]=[N:9]3)=[C:4]([O:12][CH:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH2:15][CH2:14]3)[CH:3]=1)[CH2:34]2
Reactant: C1NCC2CC1O2
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(Oc2cc(Br)cc3nccnc23)CC1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C1CCC(Oc2cc(N3CC4CC(C3)O4)cc3nccnc23)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 120 %

Procedure:
A mixture of 2-[4-(7-bromoquinoxalin-5-yl)oxycyclohexyl]isoindoline-1,3-dione (1 g, 2.211 mmol), 6-oxa-3-azabicyclo[3.1.1]heptane HCl (180 mg, 1.328 mmol), cesium carbonate (2.161 g, 6.633 mmol), Pd2(dba)3 (202.5 mg, 0.2211 mmol) and rac-BINAP (275.3 mg, 0.4422 mmol) in dioxane (5 mL) was stirred overnight at 70° C., then heated in a microwave reactor for 15 min at 150° C. The reaction was then diluted with methylene chloride, filtered though Celite, and concentrated. Silica gel flash column chromatography (0-5% MeOH/DCM) yielded 2-[4-[7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoxalin-5-yl]oxycyclohexyl]isoindoline-1,3-dione (750 mg, 72.1%) as a yellow solid that was carried on to the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[CH:5]=[C:6]([C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])[C:7]2=[O:12].C(=O)([O-])[OH:27].[Na+].OO>CO>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[CH:5]1[O:27][C:6]1([C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])[C:7]2=[O:12]
Reactant: COc1cc(C)cc(C(=O)O)c1C1=CC(=O)c2c(O)cccc2C1=O
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)cc(C(=O)O)c1C12OC1C(=O)c1c(O)cccc1C2=O
Yield: 95.5 %

Procedure:
In methanol (15 ml) was dissolved 2-(5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoic acid (100 mg) as obtained in Example 15, followed by addition of sodium hydrogen carbonate (80 mg). The mixture was stirred under ice-cooling. Then, 30% hydrogen peroxide (1.5 ml) was added dropwise and the reaction mixture was allowed to return gradually to room temperature, at which temperature it was further stirred for 5 hours. The solvent was then distilled off under reduced pressure, dilute HCl was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried by addition of magnesium sulfate and the solvent was distilled off to give 2-(5-hydroxy-2,3-epoxy-1,4-dihydronaphthalene-1,4-dion-2-yl)-3-methoxy-5-methylbenzoic acid (100 mg). m.p. 267°-268° C.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[F:18][C:19]1[CH:26]=[CH:25][C:22]([C@H:23]2[O:15][CH2:14][C@H:13]([CH2:12][CH2:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]3)[CH2:16][O:17]2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCC[C@H]1CC[C@H](CCC(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@H](CC[C@H]2CO[C@H](c3ccc(F)cc3)OC2)CC1

Procedure:
A solution of 2.4 g (0.01 mol) of 2-[2'-(trans-4"- butylcyclohexyl)ethyl]propane-1,3-diol, 1.8 g (0.01 mol) of 4-fluorobenzaldehyde (manufactured by Aldrich) and 0.1 g of TsOH in 50 cm3 of dichloromethane was refluxed for 3 hours over a hot water bath with a Dean-Stark trap. The resulting solution was washed with water and the dichloromethane was distilled off. The residue was recrystallized from a solvent mixture of acetone and methanol to yield 3.0 g (0.008 mol) of trans-2-(4'-fluorophenyl)-5-[2'-(trans-4"-butylcyclohexyl)ethyl]-1,3-dioxane. The phase transition temperature of this compound, measured by DSC, was: ##STR41## wherein C is the crystal phase, N is the nematic phase, and I is the isotropic liquid phase.