Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:16])[CH:14]=[CH2:15].C(N(CC)CC)C.ClCCl>CN(C=O)C.CCOC(C)=O.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]>[CH2:18]([O:17][C:13](=[O:16])/[CH:14]=[CH:15]/[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=CC(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1/C=C/C(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
To a solution of ethyl 2-bromobenzoate (1.15 g, 5.0 mmol) in 20 mL of DMF was added benzyl acrylate (1.22 g, 7.5 mmol) and triethylamine (1.39 mL, 10.0 mmol). The mixture was degassed and then there was added [1,1′-bis(diphenylphoshino)ferrocene]dichloropalladium (II), complex with dichloromethane (12.2 mg, 0.015 mol). The reaction mixture was stirred at 90° C. for 18 h. The reaction mixture was allowed to cool and was diluted with EtOAc. The organics were washed with water and brine, dried (MgSO4) and concentrated to an oil. The residue was purified (ISCO, elution with 0-15% EtOAc/hexane) to give 1.44 g (92%) of the title compound. 1H NMR (CDCl3): δ 8.51 (d, 1H), 7.96 (d, 1H), 7.57 (d, 1H), 7.50 (t, 1H), 7.45-7.22 (overlapping m, 6H), 6.35 (d, 1H), 5.26 (s, 2H), 4.38 (q, 2H), 1.37 (t, 3H). LRMS (ESI): 311.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][C:28]([C:31]([O:33]C)=[O:32])=[CH:27][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[ClH:37]>O1CCCC1.CO>[ClH:37].[CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(-c2cccnc2)cccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(-c2cccnc2)cccc1-3
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
To a solution of methyl 12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (130 mg, 0.203 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was adjusted to pH 6.5 with 2N hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. To a solution of the residue in chloroform was added 4N HCl-ethyl acetate solution (0.5 ml), and the solvent was evaporated under reduced pressure. A mixed solvent (hexane:ethyl acetate=4:1) was added to the residue. The precipitated solid was collected by filtration to give 12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid hydrochloride (88 mg, yield 91%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)=[CH:6][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[CH2:11][NH:10][C:8]([C:7]1[CH:6]=[C:5]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)[N:4]=[N:3][C:2]=1[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:9]
Reactant: C1CCNC1
Reactant: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)nnc2Cl)cc1OC
Solvent: C1COCCO1
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)nnc2N2CCCC2)cc1OC
Temperature: 100 °C

Procedure:
To a solution of 3-chloro-N-(3,4-dimethoxybenzyl)-6-(3,5-dimethylphenyl)pyridazine-4-carboxamide (1-3, 0.011 g, 0.027 mmol, 1.0 equiv) in dioxane (0.27 mL) was added pyrrolidine (0.038 g, 0.53 mmol, 20.0 equiv) and the reaction mixture was heated to 100° C. under microwave heating for 10 minutes. The reaction was cooled and directly purified by normal phase column chromatography (10 to 100% EtOAc in hexanes) to afford the product (1-4) as a white solid. HRMS [M+H] C26H30N4O3 calc'd 447.2391. found 447.2384.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[C:12]([Br:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>CC(O)C>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:18]2[C:13]3[C:12]([Br:20])=[CH:11][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Temperature: -10 °C
Yield: 86.9 %

Procedure:
A suspension of 7-Benzenesulfonyl-5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.9 g, 13 mmol), Piperazine-1-carboxylic acid tert-butyl ester (3.7 g, 20 mmol), and DIPEA (5.7 mL, 33 mmol) in IPA (30 mL) was stirred and heated at reflux for 6 hours. The mixture was cooled to −10° C., the solids collected by vacuum filtration, rinsed with cold IPA and dried under vacuum to give 4-(7-Benzenesulfonyl-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (5.9 g, 86%.) LCMS (APCI+) m/z 522 and 524 [M+H]+; Rt: 3.92 min. 1H NMR (DMSO-d6, 400 MHz) δ 8.48 (1H, s), 8.21 (2H, d, J 8.2 Hz), 7.66-7.62 (2H, m), 7.54 (2H, t, J 7.8 Hz), 3.62-3.55 (8H, m), 1.48 (9H, s.)
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:18]2[CH:19]=[N:20][NH:21][CH:22]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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.CCOC(C)=O>[NH:20]1[CH:19]=[C:18]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:22]=[N:21]1
Reactant: O=Cc1ccccc1Br
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1-c1cn[nH]c1
Temperature: 100 °C
Yield: 39.4 %

Procedure:
To a solution of 2-bromobenzaldehyde (300 mg, 1.62 mmol) in DMF (10 mL) are added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (470 mg, 2.43 mmol), Pd(PPh3)4 (190 mg, 0.16 mmol) and 2M Na2CO3 (0.50 mL) at room temperature. The solution is heated to 100° C. for 1 hour in a microwave reactor, cooled and poured into water and EtOAc. Layers are separated and the aqueous phase extracted with EtOAc (1×10 mL). The combined organics are dried (MgSO4), filtered and are concentrated to give the crude product which is purified via flash chromatography (12 g silica gel, 0-10% MeOH/CH2Cl2). The product-containing fractions are combined and concentrated to give 2-(1H-pyrazol-4-yl)-benzaldehyde (110 mg, 39%) which is used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)C(OC(C)(C)C)=O)[CH:9]=[CH:8][C:7]=1[Br:28])(=[O:3])[CH3:2].Cl.[OH-].[Na+]>O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([NH:12][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[CH:9]=[CH:8][C:7]=1[Br:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)ccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)OCc1cc(Nc2ccc(C#N)cc2)ccc1Br
Temperature: 0 °C

Procedure:
2-bromo-5-[N-(tert-butoxycarbonyl)-4-cyanophenylamino]benzyl acetate (3.02 g, 6.78 mmol) was treated with 4 mol/L hydrogen chloride in dioxane (20 mL) at room temperature for two hours. This was neutralized with 1 mol/L sodium hydroxide to PH=6 to 7 in ice-water bath and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-bromo-5-(4-cyanophenylamino)benzyl acetate, which was used for the next step without purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[Si:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Yield: 97 %

Procedure:
1-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)benzene was dissolved in ethyl acetate (400 ml) and 5 g of palladium on active carbon (5%) were added. After hydrogenation, the catalyst was removed by filtration and the solvents were removed under vacuo, to yield 42 g of 4-(tert-butyldimethylsilyloxy)-phenol (97%).
Reaction SMILES: C(OCC[O:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18]C(=O)C)=[C:11](Br)[CH:10]=1)(=O)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[OH:18][CH2:17][CH2:16][O:15][C:12]1[C:11]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)=[CH:10][C:9]([C:8]([OH:7])=[O:23])=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)OCCOC(=O)c1ccc(OCCOC(C)=O)c(Br)c1
Product: O=C(O)c1ccc(OCCO)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The compound of step 1 was coupled to 3-trifluoromethyl-phenylboronic acid in analogy to step 3 of example 92, the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield 6-(2-Hydroxy-ethoxy)-3′-trifluoromethyl-biphenyl-3-carboxylic acid. This intermediate was coupled to trans-1-amino-4-ethylcyclohexanecarboxylic acid methylester hydrochloride in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17](=[O:20])[CH2:18][CH3:19])[CH3:13].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)=[CH:26][CH:25]=1>O1CCCC1.O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)=[CH:28][CH:29]=1)[C:17](=[O:20])[CH2:18][CH3:19])[CH3:13]
Reactant: CCOC(=O)CC(=O)CC
Reactant: BrCc1ccc(-n2cccn2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)CC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of potassium tert-butoxide (0.57 g) in tetrahydrofuran (40 mL) at 0° C. was treated with a mixture of tert-butanol (2.0 mL) and 3-oxopentanoic acid ethyl ester (0.73 mL), and the resulting mixture was stirred at 0° C. for 45 minutes. The mixture was then treated with a solution of 1-(4-bromomethylphenyl)-1H-pyrazole (1.0 g) in tetrahydrofuran (10 mL), and stirred at 0° C. for 2 hours. The mixture was diluted with water, concentrated to low bulk under reduced pressure, and the residue extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate gave title compound as a pale yellow oil (0.63 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C@H:14]([CH2:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26])[O:13][C:12]1([CH3:32])[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:37])[CH2:34][CH2:35][CH3:36].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C@H:14]([CH2:23][C@@H:24]([CH:28]([CH3:29])[CH3:30])[C:25]([NH:37][CH2:33][CH2:34][CH2:35][CH3:36])=[O:26])[O:13][C:12]1([CH3:32])[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1)C(=O)O
Reactant: CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNC(=O)[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1)C(C)C
Reaction time: 8 h

Procedure:
The crude carboxylic acid (I) (551 mg) was dissolved in DMF (10 ml) containing triethylamine (126 mg). Butylamine (109 mg), HOBT (169 mg) and EDAC (240 mg) were added and the solution was allowed to stand overnight. The solvent was removed by evaporation and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated and washed with saturated sodium hydrogen carbonate solution (20 ml), followed by water (20 ml) and then saturated sodium chloride solution (20 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:4 v/v), to give initially (2S)-2-[(4S,5S)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidin-5-yl]methyl-N-butyl-3-methylbutanamide (J), as a clear oil (103 mg); NMR (CDCl3): 0.9 (m, 9H), 1.0-2.1 (complex m, 27H), 3.25 (q, 2H), 3.75 (m, 2H), 5.1 (dd, 2H), 5.6 (br, 1H), 7.3 (m, 5H); and then the corresponding (2R)-isomer, as a clear oil (133 mg); NMR (CDCl3): 0.9 (m, 9H), 1.0-2.1 (complex m, 27H), 3.25 (m, 2H), 3.75 (m, 1H), 3.9 (m, 1H), 5.1 (dd, 2H), 5.4 (br, 1H), 7.4 (m, 5H).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[Cl-].[S:9]1[CH:13]=[C:12]([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:11]2[CH:34]=[N:35][CH:36]=[C:10]12.[CH2:37]([O:40][C:41]([N:43]1[C@H:47]([CH:48]=O)[CH2:46][C@@H:45]([O:50][Si](C(C)(C)C)(C)C)[CH2:44]1)=[O:42])[CH:38]=[CH2:39].C(OCC)(=O)C>C1COCC1.CS(C)=O>[CH2:37]([O:40][C:41]([N:43]1[C@H:47]([CH:48]=[CH:14][C:12]2[N:11]3[CH:34]=[N:35][CH:36]=[C:10]3[S:9][CH:13]=2)[CH2:46][C@@H:45]([OH:50])[CH2:44]1)=[O:42])[CH:38]=[CH2:39]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: c1ccc([P+](Cc2csc3cncn23)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C=Cc1csc2cncn12
Reaction time: 2 h
Yield: 53.4 %

Procedure:
Potassium-t-butoxide (1.95 g) is added to a solution of 4.09 g of (imidazo[5,1-b]thiazol-3-yl)methyltriphenylphosphonium chloride hydrochloride in 15 ml of THF and 15 ml of DMSO under ice cooling. The mixture is stirred for 2 hr, a solution of 2.9 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 15 ml of THF is added thereto, and the mixture is stirred under ice cooling for 2 hr. Ethyl acetate is added to the reaction mixture, the mixture is successively washed with dilute hydrochloric acid and saturated saline, and dried over magnesium sulfate. The solvent is removed by evaporation, the residue is dissolved in 80 ml of methanol, 3.5 ml of a 5 N aqueous hydrochloric acid solution is added to the solution, and the mixture is stirred at room temperature for 12 hr. The mixture is neutralized with a 5 N aqueous sodium hydroxide solution, dichloromethane is added thereto, and the mixture is successively washed with water and saturated saline and dried over magnesium sulfate. The solvent is removed by evaporation, and the residue is purified by column chromatography on silica gel to give 1.48 g of (3R,5S)-1-allyloxycarbonyl-3-hydroxy-5-[2-(imidazo[5,1-b]thiazol-3-yl)ethenyl]pyrrolidine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[O:26]1[C:31]2[CH:32]=[CH:33][C:34]([C:36](O)=[O:37])=[CH:35][C:30]=2[O:29][CH2:28][CH2:27]1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:36]([C:34]1[CH:33]=[CH:32][C:31]3[O:26][CH2:27][CH2:28][O:29][C:30]=3[CH:35]=1)=[O:37])=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc3c(c2)OCCO3)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-{[(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 2,3-dihydrobenzo-[1,4]dioxine-6-carboxylic acid. MS calcd. for C28H24ClN3O5 [(M+H)+] 518, obsd. 518.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7][CH3:8].Cl.[CH3:26][N:27]([CH3:43])[C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][N:29]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CCOC(C)=O.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].C(Cl)Cl>[CH3:26][N:27]([CH3:43])[C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])=[CH:11][N:10]=3)[C:6]=2[O:7][CH3:8])[CH:31]=[CH:30][N:29]=1
Reactant: CN(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(-c2ccnc(N(C)C)c2)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Combined 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (80 mg, 0.202 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine hydrochloride (173 mg, 0.607 mmol), PdCl2(dppf)-CH2Cl2 adduct (16.53 mg, 0.020 mmol) and sodium bicarbonate (136 mg, 1.619 mmol) in dioxane (0.6 mL) and water (0.15 mL) was let stir for 15 min. The mixture was then capped and heated at 110° C. for 1 h in the microwave. Additional PdCl2(dppf)-CH2Cl2 adduct (17 mg) was then added and the heating continued at 110° C. for 1 h in the microwave. The reaction mixture was diluted with EtOAc, concentrated onto Celite® and purified on a 10 g NH silica gel column eluted with 10 to 100% EtOAc in hexanes to give 6-(4-(2-(dimethylamino)pyridin-4-yl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide as a brown oil. MS m/z 437 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1nccs1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nccs2)c1

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (7.45 g) and 2-bromothiazole (2.46 g) in pyridine (25 ml) were stirred under reflux for 20 hours. The reaction mixture was cooled, evaporated and partitioned between chloroform and water. The chloroform layer was evaporated and subjected to medium pressure column chromatography on silica (chloroform:methanol 19:1) to give the title compound as an oil. This was converted to 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]thiazole dihydrochloride, m.p. 192.5°-193.5° C. (recrystallised from isopropanol-ethyl acetate).
Reaction SMILES: [OH2:1].[OH2:2].[O-:3][S:4]([O-:7])(=[O:6])=[O:5].[Ca+2:8].S(=O)(=O)(O)[OH:10]>>[O:1]=[O+:2][O-:3].[OH2:10].[OH2:3].[O-:6][S:4]([O-:7])(=[O:5])=[O:3].[Ca+2:8]
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=[O+][O-]

Procedure:
The same phosphogypsum suspension having a whiteness grade equal to 65 was acidified up to pH equal to 3 by using a sulfuric acid solution. After treatment with 500 parts per millions of ozone a phosphogypsum having a whiteness grade equal to 77 was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)(=[O:12])=[O:11].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])=[C:2]([NH:1][S:27]([C:19]2[O:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:20]=2)(=[O:28])=[O:29])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1NS(=O)(=O)c1cccs1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1NS(=O)(=O)c1cccs1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
To a solution of N-(2-amino-4-chlorophenyl)thiophene-2-sulfonamide (CAS RN: 926205-90-5) (140 mg, ˜0.47 mmol) in pyridine (2.5 ml) was added benzofuran-2-sulfonyl chloride (102 mg, 0.47 mmol) and the mixture was stirred at room temperature for 16 h. More benzofuran-2-sulfonyl chloride (51 mg, 0.24 mmol) was added and the reaction was stirred for another 24 h, concentrated in vacuo to remove most of solvent. The residual thick syrup was quenched with 6M HCl and diluted with H2O. The resulting suspension was filtered and washed with H2O (×3). The crude product was purified by flash column chromatography on silica gel (25-50% EtOAc-hexane) to yield 43 mg of product slightly contaminated with impurities. This material was triturated with CH2Cl2 to form a sandy colored solid, which was filtered and rinsed with minimal amount of CH2Cl2 to yield 23 mg (10%) of Compound 24.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=[O:16])[N:13]=[CH:12][NH:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:7]2[C:15]3[C:14]([O:16][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cccc(OCCCBr)c1
Reactant: O=c1nc[nH]c2scc(-c3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(OCCCOc2ncnc3scc(-c4ccccc4)c23)c1
Temperature: 90 °C
Yield: 66 %

Procedure:
A mixture of 5-phenylthieno[2,3-d]pyrimidin-4(1H)-one (0.023 g, 0.10 mmol), N-[3-(3-bromopropoxy)phenyl]acetamide (0.0274 g, 0.10 mmol), potassium carbonate (0.0418 g, 0.30 mmol) and N,N-dimethylformamide (1.0 mL) was heated to 90° C. for 6 h. The reaction was then allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate (30 mL), water (30 mL) was added, and the organic layer was separated, Concentration, followed by followed by silica gel column chromatography purification (using 1.50% methanol in 1:1 ethyl acetate/hexane and ammonia (0.03%) as eluent) afforded N-(3-{3-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}phenyl)acetamide in 66% yield. N-{4-[3-(4-oxo-5-phenylthieno[2,3-d]pyrimidin-1(4H)-yl)propoxy]phenyl}acetamide was also formed in 12% yield during the reaction.