Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].CC(C)=O.C(Cl)Cl>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([Cl:23])=[CH:16][CH:17]=[CH:18][C:19]=2[NH2:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2c(N)cccc2Cl)CC1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of 342 mg (1 mmol) of 4-(2-chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 5.0 mL of MeOH was treated with 630 mg (10 mmol, 10 eq) of ammonium formate and a catalytic amount of 10% Pd—C (34 mg). The reaction mixture was stirred at 65° C. for 30 min. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. TLC (silica, 5% acetone/CH2Cl2): Rf=0.40. MS (electrospray): exact mass calculated for C15H22ClN3O2, 311.14; m/z found, 312.1 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11]O)[CH:2]=1.[Br:13]P(Br)Br>ClCCl>[Br:13][CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: BrP(Br)Br
Reactant: OCc1cnc2ccccc2c1
Solvent: ClCCl
Product: BrCc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Quinolin-3-ylmethanol was dissolved dichloromethane (15 mL) at 0° C. under nitrogen. Tribromophosphane (2.15 mL, 22 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by addition of 10% NaHCO3 solution (5 mL). After 10 minutes, Na2SO4 (30 g) was added. The solvent was filtered and evaporated to provide 3-(bromomethyl)quinoline, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13][OH:14])[C:9]([F:12])([F:11])[F:10])=[C:4](F)[CH:3]=1.C1COCC1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]([C:9]([F:12])([F:11])[F:10])=[N:13][O:14][C:4]=2[CH:3]=1
Reactant: ON=C(c1ccc(Br)cc1F)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: FC(F)(F)c1noc2cc(Br)ccc12
Temperature: 150 °C
Yield: 66.1 %

Procedure:
A solution consisting of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone oxime (3.2 g, 11.2 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.1 mL, 7.4 mmol) and THF (42 mL) was heated at 150° C. via microwave irradiation for 30 min. The reaction mixture was diluted with CH2Cl2 (25 mL) and washed with HCl (1 N aq., 25 mL). The organic layer was then dried (Na2SO4), concentrated, and purified (FCC) to yield the title compound (1.97 g, 66%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@@H:14](/[CH:30]=[CH:31]/[CH2:32][C:33]([N:35]1[C@@H:39]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:38][O:37][C:36]1=[O:47])=[O:34])[C:15]([N:17]1[C@@H:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][O:19][C:18]1=[O:29])=[O:16])[CH:12]=[CH2:13].[CH2:48]([O:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62]Br)=[CH:58][CH:57]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1COCC1>[CH2:11]([C@@H:14](/[CH:30]=[CH:31]/[C@H:32]([CH2:62][C:59]1[CH:60]=[CH:61][C:56]([O:55][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:57][CH:58]=1)[C:33]([N:35]1[C@@H:39]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:38][O:37][C:36]1=[O:47])=[O:34])[C:15]([N:17]1[C@@H:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:20][O:19][C:18]1=[O:29])=[O:16])[CH:12]=[CH2:13]
Reactant: C=CC[C@@H](/C=C/CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](/C=C/[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 28.5 %

Procedure:
A solution of NaHMDS (1.0 M in THF, 0.258 mL, 0.258 mmol) was added dropwise to a −78° C. solution of (S,E)-2-allyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)hex-3-ene-1,6-dione (118 mg, 0.235 mmol) in THF (1.0 mL). After stirring at −78° C. for 40 min, a solution of 1-(benzyloxy)-4-(bromomethyl)benzene (78 mg, 0.282 mmol) in THF (0.2 mL) was added dropwise. The reaction temperature was then slowly raised to 0° C. over 45 min. After 30 min at 0° C., the reaction temperature was allowed to reach rt. After 2 h at rt, the reaction mixture was quenched by addition of saturated NH4Cl. The mixture was partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4 and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (2S,5S,E)-2-allyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-(4-(benzyloxy)benzyl)hex-3-ene-1,6-dione (47 mg, 0.067 mmol, 29%) as a white solid. Anal. Calcd. for C43H42N2O7 m/z 698.2. found: 699.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][CH:13]([CH:22]([C:27](OC)=[O:28])[C:23]([O:25][CH3:26])=[O:24])[C:14]1[CH:19]=[CH:18][C:17](OC)=[CH:16][CH:15]=1.[CH3:31][O-:32].[Na+].Cl>CO>[CH3:26][O:25][C:23]([CH:22]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[O:32][CH3:31])[CH2:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[NH:1][C:27]1=[O:28])=[O:24]
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1N)c1ccc(OC)cc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccccc1OC
Temperature: 0 °C

Procedure:
Under an argon atmosphere, a stirred solution of [2-(2-amino-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (20.0 g; 0.047 mol) in 200 ml of methanol was treated with 13.3 ml of 25% sodium methoxide in methanol and heated to reflux. After about 2.75 hours of heating, the mixture was cooled in ice water and 1N hydrochloric acid was added to precipitate the product. Stirring in an ice water bath, followed by filtering, washing with water and air-drying yielded 19.0 g of product. The product was suspended in 30 ml of isopropanol, allowed to stand for one hour, filtered and washed with isopropanol and hexane to yield 13.64 g of the title compound, melting point 161°-163° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:35](B1OB(C=C)OB(C=C)O1)=[CH2:36].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24]([CH:35]=[CH2:36])=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(Br)cnc4cc3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1cnc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Reaction time: 0.5 h

Procedure:
133 mg (0.256 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-1, 61.6 mg (0.256 mmol) 2,4,6-trivinyl-cyclotriboroxane, 29.6 mg (0.026 mmol) tetrakis triphenylphosphine palladium(0) and 35.4 mg (0.256 mmol) potassium carbonate in 2 mL dimethoxyethane and 0.7 mL water were heated in a microwave vial (heating block) at 110° C. for 16 hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed with brine, dried, and the solvent was removed. The crude product (168 mg>100%) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH2:36][CH2:37][NH2:38])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:38][CH2:37][CH2:36][C:30]1[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[CH:29]=1)=[O:20]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(CCNC(=O)C2=C(C(=O)Nc3cc(OC4CCCC4)c(Cl)cc3F)CCCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), 2-(3,4-dimethoxyphenyl)ethylamine (0.600 g, 3.31 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (20. ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{2-(3,4-dimethoxyphenyl)ethyl}-3,4,5,6-tetrahydrophthalamide as white crystals (1.16 g, 77.5% yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[N:3]=[CH:2]1.Cl[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>CN(C=O)C>[C:13]1([C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:1]2[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[N:3]=[CH:2]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 104 %

Procedure:
A solution of the product from Step 4.a. (3.2 g, 17.5 mmol) in DMF (50 ml) was treated with chlorotriphenylmethane (4.88 g, 17.5 mmol) and Et3N (5.4 ml, 38.5 mmol) and the reaction was stirred at room temperature for about 6 hours. The DMF was evaporated under reduced pressure and the residue was distributed between EtOAc and saturated NaCl solution. The EtOAc layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield product as a viscous oil (6.96 g, 104%) which crystallized on standing. Mass spec. 383.3 MH+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15]I)=[CH:9][CH:10]=2)[N:5]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[CH:23][CH:22]=1)#[N:2].[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1.[Na]>CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)=[CH:9][CH:10]=2)[N:5]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[CH:23][CH:22]=1)#[N:2]
Reactant: c1nc[nH]n1
Reactant: CC(C)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCI)cc3n2C2CCC2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCn4cncn4)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To 1 mL of the DMF solution above, 1-{4-[3-cyano-1-cyclobutyl-6-(3-iodopropoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea (34 mg, 0.062 mmol) is added anhydrous 1,2,4-triazole, sodium salt (10.0 mg, 0.110 mmol). After stirring overnight at rt, the reaction mixture is filtered and purified by preparatory LC/UV purification. The solvent is removed to obtain 12.3 mg (40%) of 1-{4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea (compound 1314), as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[P:13]([O-:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[K+].CCOC(C)=O>C1COCC1>[C:21]([O:20][P:13]([O:25][CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1
Temperature: 70 °C
Yield: 45 %

Procedure:
To a stirred solution of methyl-3-(bromomethyl)benzoate (0.5 g, 2 mmol) in THF (10 mL) was added potassium ditertiary butyl phosphate (0.5 g, 2 mmol). The reaction flask was heated to 70° C. for 2 h. After the flask was cooled to rt, EtOAc (50 mL) was added to the mixture. The organics were washed with brine (2×10 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to yield methyl 3-((di-tert-butoxyphosphoryloxy)methyl)benzoate (0.35 g, 0.9 mmol). 1H NMR (400 MHz, CHCl3-d): δ 1.47 (s, 18H), 3.91 (s, 3H), 5.03 (d, 2H, J=7.6 Hz), 7.44 (t, J=7.6 1H), 7.60 (dd, J=1.2 and 7.2), 7.98 (ddd, J=1.2, 2.8 and 7.6, 1H), 8.05 (t, J=0.4, 1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Zn+].C1COCC1.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]3([C:29]([NH:31][C:32]4[N:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=4)=[O:30])[CH2:28][CH2:27]3)=[CH:25][C:20]=2[O:19][CH2:18]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]3([C:29]([NH:31][C:32]4[N:33]=[N:34][C:35]([CH2:6][C:5]5[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=5[O:3][CH3:2])=[CH:36][CH:37]=4)=[O:30])[CH2:28][CH2:27]3)=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: COc1ccccc1C[Zn+]
Reactant: O=C(Nc1ccc(Cl)nn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccccc1Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nn1
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a 0.5 M solution of (2-methoxybenzyl)zinc(II) chloride in THF (0.8 mL, 0.4 mmol) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg, 0.01 mmol) and the reaction was stirred under nitrogen for 20 minutes. 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-chloropyridazin-3-yl)cyclopropanecarboxamide (32 mg, 0.1 mmol) was added and the reaction was irradiated in the microwave for 10 minutes at 150° C. The reaction was quenched with a saturated ammonium chloride solution (2 mL) and a saturated ethylenediamine tetraacetic acid disodium salt solution (2 mL). The mixture was stirred for 30 minutes before it was extracted with dichloromethane (3×4 mL). The organics were dried over Na2SO4 and evaporated. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product (21 mg, 0.052 mmol, 52%). ESI-MS m/z calc. 379.2, found 380.3 (M+1)+; retention time 3.54 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15]O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P(Br)(Br)[Br:18].O>O1CCCC1.C(OCC)(=O)C>[Br:18][CH2:15][CH2:14][CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: BrP(Br)Br
Reactant: COc1cc(CCCO)cc(OC)c1OC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CCCBr)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
To a solution of 3-(3,4,5-trimethoxyphenyl)-propan-1-ol (9.50 g, 0.042 mol) in 50 ml of tetrahydrofuran, 5.0 ml (0.053 mol) of phosphorus tribromide were added dropwise at 0° C., followed by stirring at room temperature for 12 hours. The reaction mixture was added with water under ice cooling. The resulting solution was dissolved in 200 ml of ethyl acetate. The orqanic layer was washed successively with water, saturated NaHCO3 and saturated NaCl and then dried over anhydrous magnesium sulfate. The solvent was thereafter distilled off under reduced pressure. The oil thus obtained was purified by column chromatography (silica gel: "MERCK #9385", eluent: ether), whereby 10.2 g of the title compound were obtained as colorless oil (yield: 84%).
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([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.O.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>[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][C:2]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:3]3)[CH2:14][CH2:15]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccccn4)nc32)CC1
Temperature: 100 °C

Procedure:
To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (50 mg, 0.12 mmoles) in toluene (500 μL) in a screw-capped vial under argon are added 2-(tributylstannyl)pyridine (77 μL, 0.24 mmole), tetrakis(triphenylphosphine)palladium(0) (14 mg, 12 μmole). The reaction mixture is heated at 100° C. overnight. A solution of 10% KF in water is added, and the aqueous phase is extracted three times with CH2Cl2. The organic phase is washed with a solution of 10% KF in water, brine, 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 (99:1:0.1) 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-pyridin-2-yl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([C:9](OC)=[O:10])=[CH:5][N:4]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1
Reactant: COC(=O)c1cnc(SC)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CSc1ncc(CO)cn1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of methyl 2-(methylsulfanyl)pyrimidine-5-carboxylate (N1) (023 g, 1.2 mmol) in 20 mL THF at −78° C. was added diisobutylaluminum hydride (3.2 mL, 1.0 M solution in toluene). The reaction mixture stirred for 40 min at −78° C., and then additional diisobutylaluminum hydride (5 eq.) was added dropwise. The reaction mixture was stirred for 2 h, and then quenched with concentrated acetic acid. The reaction mixture was warmed to room temperature and filtered to obtain a biphasic solution. The layers were separated, and the organics were dried over sodium sulfate, filtered, and concentrated to afford [2-(methylsulfanyl)pyrimidin-5-yl]methanol (N2) that gave a mass ion (ES+) of 157.1 for M+H+.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16]CC(C)(C)C(O)=O)=[CH:14][N:15]=1.C(Br)C1C=CC=CC=1.C([O:46][C:47](=[O:58])[C:48](SC1SC(N)=NC=1)([CH3:50])[CH3:49])C>>[CH2:4]([O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][C:48]([CH3:50])([CH3:49])[C:47]([OH:58])=[O:46])=[CH:14][N:15]=1)[C:3]1[CH:2]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Agent: BrCc1ccccc1
Product: CC(C)(Sc1cnc(NC(=O)N(CCOCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using benzyl bromide and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)[C:20](=O)[CH:21]([CH3:23])[CH3:22])C.O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=1)=[C:20]([CH:21]([CH3:22])[CH3:23])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)C(C)C
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2[nH]c(C(C)C)c(Cc3ccc(S(C)(=O)=O)cc3)c(=O)c12
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.70 g), 2-(4-methanesulfonylbenzyl)-4-methyl-3-oxopentanoic acid ethyl ester (1.4 g), polyphosphoric acid (3.5 g) and dioxane (50 mL) was heated at 120° C. for 2 days. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:1 by volume) to afford title compound. 0.79 g.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[N+:36]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]O)([O-:38])=[O:37]>O1CCCC1>[C:32]([O:31][C:29]([N:20]([CH2:42][C:41]1[CH:44]=[CH:45][CH:46]=[C:39]([N+:36]([O-:38])=[O:37])[CH:40]=1)[NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: O=[N+]([O-])c1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
To a solution of triphenylphosphine (2.06 g) in tetrahydrofuran (20 ml), a solution of di-t-butyl azodicarboxylate (1.80 g) in tetrahydrofuran (15 ml) was added dropwise under ice cooling and stirred for 15 min. To the reaction mixture, a solution of m-nitrobenzyl alcohol (1.0 g) in tetrahydrofuran (15 ml) was added dropwise and stirred at room temperature for 63 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 2.25 g of the titled compound (yield, 94%).