Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12.ClC1N=NC(N2CCN(C3C=CC(C(F)(F)F)=CN=3)CC2)=C2OC=CC=12.[Br-].[CH2:54]([Zn+])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>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>[CH2:54]([C:2]1[N:3]=[N:4][C:5]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][N:18]=3)[CH2:15][CH2:16]2)=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: FC(F)(F)c1ccc(N2CCN(c3nnc(Cl)c4occc34)CC2)nc1
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: FC(F)(F)c1ccc(N2CCN(c3nnc(Cl)c4ccoc34)CC2)nc1
Agent: [Br-]
Product: FC(F)(F)c1ccc(N2CCN(c3nnc(Cc4ccccc4)c4occc34)CC2)nc1
Temperature: 80 °C
Yield: 7 %

Procedure:
The mixture of 7-chloro-4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-furo[2,3-d]pyridazine and 4-chloro-7-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-furo[2,3-d]pyridazine (210 mg, 0.547 mmol) are combined with benzyl zinc bromide (6.75 mL, 0.5M in THF, 3.28 mmol) and tetrakis (triphenylphosphine) palladium0 (31.5 mg, 0.027 mmol). The reaction is heated to 80° C. for 40 h. Add H2O and extract with EtOAc. Concentrate in vacuo. The residue is purified by flash chromatography on silica gel (EtOAc/Heptane) to afford a mix of title compounds. This mixture is separated by HPLC using a 30% isocratic gradient of CH3CN/H2O with a formic acid modifier (0.1%) to yield both title compounds (16.9 mg, 7%).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[Mg].Br[C:21]1[CH:25]=[CH:24][O:23][CH:22]=1.[OH-].[NH4+]>C1COCC1.BrC(Br)C.C1(C)C=CC=CC=1.C1C=CC([P]([Ni]([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.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reactant: Brc1ccoc1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Ni]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(-c3ccoc3)c2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.2 mmol) was dissolved in 20 ml of THF, and 94 mg (3.9 mmol) of magnesium shavings were added. The mixture was refluxed, and a couple of drops of dibromoethane were added to initiate Grignard formation. The mixture was refluxed for one hour after which it was added to a solution of 0.58 ml (6.4 mmol) of 3-bromofuran and 36 mg (0.03 mmol) of Ni(PPh3)4 in 20 ml of toluene that had been cooled to 0° C. after stirring at room temperature for one hour. The mixture was stirred at room temperature for three hours after which an additional 0.58 ml of 3-bromofuran and 35 mg of Ni(PPh3)4 were added. When the reaction failed to proceed further, 210 mg (0.3 mmol) Ni(PPh3)2Cl2 was added, and the mixture was stirred overnight at room temperature. The mixture then was poured into water and the pH adjusted to 10 with ammonium hydroxide. The mixture was extracted with methylene chloride, dried over sodium sulfate, and evaporated to give 0.8 g of a residue.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[CH3:34][N:35]([CH3:45])[CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:42]5[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:34])[CH3:45])[CH2:40][CH2:41]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: CN(C)CCCN1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 1-(3-dimethylaminopropyl)piperazine. A yellow solid 134 was obtained (0.0401 g, 73%). MS (APCI) m/z 559 (M+H)+.
Reaction SMILES: [OH-].[Na+].C(OC(=O)[CH2:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])[N:11]=[N:10][CH:9]=1)C.Cl>CO>[CH2:21]([C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:11]=[N:10][CH:9]=[C:8]([CH3:7])[CH:13]=2)=[C:15]([CH3:40])[CH:16]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCOC(=O)Cc1cnnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cc(C)cnn2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.010 mL) was added to a solution of [6-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridazin-4-yl]acetic acid ethyl ester (Example 183-(4); 2.5 mg, 0.0047 mmol) in methanol (0.10 mL) at room temperature, and the mixture was stirred at room temperature for four hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=1/2) to give the title compound (1.8 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[N:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]=[O:27]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:26]([NH:25][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CN=C=O
Product: CCOC(=O)CNC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 27 %

Procedure:
According to the procedure of Example 71, (1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with ethyl isocyanato-acetate. The crude product is purified by column chromatography (silica gel, 1:4 ethyl acetate:methylene chloride) to give pure N-[[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]carbonyl]glycine, ethyl ester (27%) as an amorphous solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[C:12]([Cl:21])=[N:13][C:14]2[N:15]([N:18]=[CH:19][CH:20]=2)[C:16]=1Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][O:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1>C(O)(C)C>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[C:12]([Cl:21])=[N:13][C:14]2[N:15]([N:18]=[CH:19][CH:20]=2)[C:16]=1[NH:40][C:37]1[CH:36]=[CH:35][C:34]([O:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:39][CH:38]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1c(Cl)nc2ccnn2c1Cl
Reactant: COCCOc1ccc(N)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COCCOc1ccc(Nc2c(CCO[Si](C)(C)C(C)(C)C)c(Cl)nc3ccnn23)cc1
Temperature: 85 °C

Procedure:
To an isopropanol (3.0 mL) solution containing 6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5,7-dichloropyrazolo[1,5-a]pyrimidine (512 mg, 1.49 mmol), triethylamine (836 μL, 5.96 mmol) and 4-(2-methoxyethoxy)phenylamine (299 mg, 1.79 mmol) were added, and this mixture was heated at 85° C. with stirring. After the reaction, the solvent was concentrated, sodium hydrogen carbonate was added here, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[C:10]([CH3:17])=[N:9]2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:23]([CH:26]=1)[C:24]#[N:25].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:14]([C:11]2[C:10]([CH3:17])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:20]=[CH:21][C:22]=1[O:27][CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])#[N:25]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1nn(-c2ccc(F)cc2)c(C)c1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(-c2ccc(F)cc2)c(C)c1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
1-(4-Fluorophenyl)-3,5-dimethylpyrazole-4-carboxylic acid (2 g), 5-amino-2-neopentyloxybenzonitrile (1.7 g), triethylamine (1.7 g) and diethyl cyanophosphate (1.4 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.6 g), melting point: 174–175° C.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].C(S([C:12]1[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])=[O:18])=[CH:15][N:16]=1)=O)C>O1CCCC1>[O:5]1[CH:4]([CH2:6][O:7][C:12]2[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])=[O:18])=[CH:15][N:16]=2)[CH2:3]1
Reactant: C#CCCCCNC(=O)c1cnc(S(=O)CC)s1
Reactant: OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCCNC(=O)c1cnc(OCC2CO2)s1
Temperature: -5 °C

Procedure:
In this preparation 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole glycidol is added dropwise. The mixture is allowed to warm -5° C and stirred for 10 minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfinyl-5-(hex-5-ynylaminocarbonyl)thiazole in 100 ml. of anhydrous tetradrofuran is added dropwise and the resulting solvent is added as needed to facilitate stirring. The mixture is maintained for 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording an oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate-60% hexane, by vol., affording 1,2-epoxy-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane.
Reaction SMILES: C[O:2][C:3]1[CH2:12][C:11]2[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]4[N:33]=[C:32]5[C:27]([CH2:28][CH2:29][C:30](=[O:34])[NH:31]5)=[CH:26][CH:25]=4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH:4]=1>C(O)C.Cl>[O:2]=[C:3]1[CH2:12][C:11]2[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]4[N:33]=[C:32]5[C:27]([CH2:28][CH2:29][C:30](=[O:34])[NH:31]5)=[CH:26][CH:25]=4)[CH2:17][CH2:18]3)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: COC1=CCc2cccc(N3CCN(CCCCOc4ccc5c(n4)NC(=O)CC5)CC3)c2C1
Agent: Cl
Solvent: CCO
Product: O=C1CCc2cccc(N3CCN(CCCCOc4ccc5c(n4)NC(=O)CC5)CC3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
7-{4-[4-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (325 mg, 0.704 mmol) was dissolved in ethanol (5 mL) and 10% HCl (1 mL). The mixture was stirred at room temperature for 2 hours then quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The crude solid was purified by column chromatography (2:98 methanol/ethyl acetate) to yield the title compound (180 mg, 57%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.38 (d, 1H), 7.20 (t, 1H), 7.02–6.96 (m, 2H), 6.36 (d, 1H), 4.20 (t, 2H), 3.60 (s, 2H), 2.06 (t, 2H), 3.00–2.80 (m, 6H), 2.80–2.40 (m, 10H), 1.80–1.60 (4H); MS ES+ 449.06 (M+H)+ (Exact mass: 448.25).
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].S(=O)(=O)(O)O>C(#N)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Yield: 108.4 %

Procedure:
To a 500 mL flask, ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (22.22 g, 90%, 60 mmol), potassium persulfate (25.92 g, 96 mmol) and acetonitrile (180 mL) were added. The reaction mixture was stirred at room temperature. The concentrated sulfuric acid (12 g) was added dropwise. After added completely, the reaction mixture was heated to reflux for 2 hours. The mixture was concentrated by rotary evaporator to remove most acetonitrile. Water (100 mL) was added and then the mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator to give the product (21.50 g) as a yellow solid in 90% yield. HPLC area normalization method content is 83%.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:10](=[O:11])[O:9][CH:8]([CH2:12]OC(=O)C)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH:5]1[CH2:6][CH2:7][CH:8]([CH3:12])[O:9][C:10]1=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CCC(OC(C)=O)C(=O)O1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OC1CCC(C)OC1=O
Temperature: 50 °C
Yield: 70 %

Procedure:
Acetic acid 5-acetoxy-6-oxo-tetrahydro-pyran-2-ylmethyl ester (2.3) (2.30 g, 10.0 mmol) was dissolved in ethyl acetate (50 mL) and added to the Parr reactor, followed by Pd/C (5%, 0.2 g) and triethylamine (4.3 mL, 30.0 mmol). The mixture was stirred under hydrogen (5×106 Pa) and heated at 50° C. for 1 day. The product was filtered through celite and the solvent removed under vacuum. The crude product was dissolved in CH2Cl2 (200 mL) and washed with water (3×200 mL). The solvent was removed and the resulting product dried under vacuum. The resulting syrup was sublimed under vacuum, at 50° C., affording white crystals (1.20 g, 7.0 mmol, 70%). 1H NMR (400 MHz, CDCl3) δ 5.46 (1H, dd, 3JH—H=10.56 Hz, 3JH—H=8.87 Hz, H-2), 4.60 (1H, m, H-5), 2.36 (1H, m, H-3), 2.20 (3H, s, COCH3), 2.12-2.00 (1H, m, H-4), 2.00-1.88 (1H, m, H-3′), 1.88-1.75 (1H, m, H-4′), 1.42 (3H, d, 3JH—H=6.22 Hz, H-6) ppm. 13C {1H} NMR (125 MHz, CDCl3) δ 169.9, 169.6 (COCH3, C-1), 74.2 (C-5), 66.0 (C-2), 27.8 (C-4), 23.0 (C-3), 21.0 (C-6), 20.8 (COCH3) ppm. m/z (CI-ammonia gas): 190 [M+NH4+]. Anal. Calcd for C8H12O4: C, 55.81; H, 7.02. Found: C, 55.81; H, 7.05.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH:13]1([B-](F)(F)F)[CH2:15][CH2:14]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC>[CH:13]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH2:15][CH2:14]1
Reactant: F[B-](F)(F)C1CC1
Reactant: Brc1cnccc1OCC1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc(OCC2CC2)c(C2CC2)cn1
Temperature: 115 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
To a solution of 3-Bromo-4-cyclopropylmethoxy-pyridine (Example 42a, 4.1 g, 18.0 mmol) in a mixture of toluene (55 ml) and water (6.5 ml) was added potassium cyclopropyltrifluoroborate (CAN 1065010-87-8, 2.79 g, 18.9 mmol), palladium(II) acetate (80.7 mg, 360 μmol), butyldi-1-adamantylphosphine (CAN 321921-71-5, 193 mg, 539 μmol) and cesium carbonate (14.6 g, 44.9 mmol). The reaction mixture was stirred at 115° C. for 16 h, cooled down to room temperature and filtered through a pad of celite. The filtrate was poured into a separatory funnel, diluted with ethylacetate and extracted with water. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude was purified by flash chromatography on silica eluting with a heptane/(solution 3% triethylamine in ethylacetate) gradient to yield the title compound (2.67 gr, 78.5%) as a yellow oil. MS (ESI, m/z): 190.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.B(F)(F)F.CCOCC>ClC1C=CC=CC=1>[OH:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:18](=[O:19])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: COc1cccc(O)c1
Agent: FB(F)F
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: COc1ccc(C(=O)Cc2ccc(O)cc2)c(O)c1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
A suspension of 3-methoxyphenol (44.69 kg, 360 mol) and 4-hydroxyphenylacetic acid (68.5 kg, 450 mol) in 144 L of chlorobenzene was purged with nitrogen gas. Boron trifluoride diethyl etherate (177 L, 1440 mol) was added at 20 to 25° C. The suspension was heated to 80° C. and stirred for 4 to 5 h then cooled to 5 to 10° C. and stirred overnight.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH2:23]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>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>[CH3:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][CH:32]=1
Reactant: Cc1ccc(C)c(Br)c1
Reactant: CCCCCCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOc1ccc(-c2cc(C)ccc2C)cc1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
Bromo-p-xylene (8.3 g, 45 mmol) (cf. A1 a)), K2CO3 (12.4 g, 90 mmol), 70 ml of toluene and 70 ml of H2O were placed in a reaction vessel and argon was passed in for 30 minutes. 4-hexyloxyphenylboronic acid (10 g, 45 mmol) and Pd(PPh3)4 (0.65 g, 0.56 mmol) were subsequently added under protective gas. The yellow-green, turbid mixture was stirred vigorously under a blanket of protective gas for about 20 hours at an internal temperature of 85° C. After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtering off any palladium residues, the solution was evaporated. The crude product was purified by distillation under reduced pressure: the product was obtained as a yellow oil (boiling point: 117°-125° C./0.08 mbar): 10.3 g (81%). Purity >95% (1H-NMR).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:23]5=[N:24][S:25](=[O:29])(=[O:28])[CH2:26][CH2:27][N:22]5[CH:21]=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>C1COCC1>[O:29]=[S:25]1(=[O:28])[CH2:26][CH2:27][N:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH:8]4[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]4)=[CH:17][CH:16]=3)[C:23]2=[N:24]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CCC5(CC4)OCCO5)cc3)C2=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCC(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A mixture of 9-[4-(1,4-dioxaspiro[4.5]dec-8-yloxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (130 mg), 1M hydrochloric acid (15 mL) and dehydrated THF (15 ml) was stirred at room temperature for 8 hr. The reaction mixture was neutralized with 1M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give the title compound (109 mg) as a pale-yellow solid.