Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:27])[NH:4][C:5]1[CH:21]=[CH:20][C:19]2[C:10]3[NH:11][C:12](=[O:18])[C:13]4[N:14]([CH:15]=[CH:16][N:17]=4)[C:9]=3[CH:8]([CH2:22][C:23]([O:25]C)=[O:24])[C:7]=2[CH:6]=1.[OH-].[Na+].Cl>>[CH3:1][NH:2][C:3](=[O:27])[NH:4][C:5]1[CH:21]=[CH:20][C:19]2[C:10]3[NH:11][C:12](=[O:18])[C:13]4[N:14]([CH:15]=[CH:16][N:17]=4)[C:9]=3[CH:8]([CH2:22][C:23]([OH:25])=[O:24])[C:7]=2[CH:6]=1
Reactant: CNC(=O)Nc1ccc2c(c1)C(CC(=O)OC)c1c-2[nH]c(=O)c2nccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)Nc1ccc2c(c1)C(CC(=O)O)c1c-2[nH]c(=O)c2nccn12
Temperature: 35 °C
Yield: 45.7 %

Procedure:
A mixture of 0.75 g of methyl [8-(3-methylureido)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-10-yl]acetate and 4 ml of 1N sodium hydroxide is heated at a temperature in the region of 35° C. for 2 hours. The mixture is acidified with 1N hydrochloric acid and the precipitate formed is filtered off, washed with distilled water and dried at 60° C. under vacuum (1 mmHg; 0.13 kPa). 0.33 g of [8-(3-methylureido)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-10-yl]acetic acid is obtained in the form of a yellow solid melting above 260° C. (Analysis, % calculated C: 57.79, H: 4.28, N: 19.82, O: 18.11, % found C: 57.8, H: 4.3, N: 19.8).
Reaction SMILES: C([O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)C>C(Cl)Cl>[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1
Reactant: CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Solvent: ClCCl
Product: NS(=O)(=O)c1nc2ccc(O)cc2s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
A 1 M solution of BBR in MCH2C12 (23 ml., 0.022 mol) was cooled to -80° C. in a dry ice/acetone bath stirred for 20 minutes. (The reaction was accomplished under a nitrogen atmosphere.) A suspension of 6-ethoxy-2-benzothiazolesulfonamide (0.5g., 0.002 mol) in 75 ml of CH2Cl2 was added slowly to the coole bath and stirred at room temperature overnight. The reaction was poured into ice water and filtered to yield 0.35 g of product (73.8% yield). The product was purified by recrystallization from methanol and water. m.p. 209° C.; NMR(DMSO-D6), δ8.4 (s, lH), 8.3-7.0 (m, 3H), 3.5 (s, 2H); DMSO-D6 /D2O)6 δ8.3-7.0 (m, 3H), 4.2 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[OH-].[K+].Cl[CH2:22][C:23]1[CH:35]=[CH:34][C:26]2[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:25]=2[CH:24]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:24]1[C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][C:26]=2[CH:34]=[CH:35][C:23]=1[CH2:22][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18]
Reactant: ClCc1ccc2oc3ccccc3c2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2ccc3oc4ccccc4c3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 8 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (75 mg, 303 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.15 mL, 0.30 mmol) at RT followed by 2-(chloromethyl)dibenzo[b,d]furan CCH 34116-2 (70 mg, 323 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4) gave, after evaporation and drying, 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol (11 mg, 8% yield). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.20 M HCl solution in MeOH (0.25 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol hydrochloride 7 as a pale brown solid (11 mg, 8% yield).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[N:27]2[CH2:28][CH2:29][N:30]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=3)[CH2:31][CH2:32]2)=[CH:38][CH:37]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)n(-c2ccccc2)n1

Procedure:
157 mg (92%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (75 mg, 0.310 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (89 mg, 0.310 mmol), DIPEA (0.081 mL, 0.465 mmol) and NaBH(OAc)3 (197 mg, 0.930 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20](=[O:22])[CH3:21])[C@@H:15]([CH3:23])[CH2:14][C@H:13]3[NH2:24])=[C:6]([CH3:25])[CH:5]=1.C(N(CC)CC)C.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.B(O)O.O.N>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH3:16].[C:20]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:26])=[CH:5][C:6]=3[CH3:25])=[CH:19][CH:18]=2)[C@H:13]([NH:24][C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)[CH2:14][C@@H:15]1[CH3:23])(=[O:22])[CH3:21]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)c(C)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2cccnc2)C[C@H](C)N3C(C)=O)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
Methyl-4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-3-methylbenzoate (for a preparation see Intermediate 96) (40 mg, 0.113 mmol) was dissolved in dichloromethane (DCM) (1.5 mL) and treated with copper(II) acetate (30.9 mg, 0.170 mmol) and triethylamine (0.047 mL, 0.340 mmol) The resulting mixture was stirred at room temperature for a few minutes then pyridine-3-boronic acid (41.9 mg, 0.340 mmol) was added. After 5 h, further boronic acid (3.5 mg, 0.028 mmol, 0.25 eq) was added and the mixture stirred at room temperature. The stirring was continued for 7 days with 10 additions of pyridine-3-boronic acid (41.9 mg, 0.340 mmol) at regular intervals (except on day 4 and day 5). The reaction mixture was then treated with a 3:1 water/ammonia 0.88 (1 mL), then was stirred for 10 min before being diluted with DCM (20 mL). The layers were separated and the organic phase was washed with a saturated NaHCO3 aqueous solution. The combined aqueous phases were extracted with DCM (20 mL). The combined organic phases were dried using a hydrophobic frit and then concentrated in vacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient:50 to 100% AcOEt in Hexanes then 0 to 10% (2M NH3 in MeOH) in DCM) gave Methyl 4-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-3-methylbenzoate (25 mg, 50%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:5]2[N:17]=[CH:18][CH:19]=[C:4]2[N:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:5]2[N:17]=[CH:18][CH:19]=[C:4]2[N:3]=1
Reactant: Cc1ccc(-c2c(CO)c(C)nc3ccnn23)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(-c2c(C=O)c(C)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a stirred solution of (5-methyl-7-p-tolylpyrazolo[1,5-a]pyrimidin-6-yl)methanol (300 mg, 1.18 mmol) in CH2Cl2 (24 mL) was added PCC (383 mg, 1.78 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by silica gel chromatography to give the title compound (212 mg, 71.2%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8](N)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[OH2:22].C=O>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([OH:22])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O
Reactant: CCC1(CC(=O)OC)OCC(N)c2c1[nH]c1ccccc21
Agent: C=O
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC)OCC(O)c2c1[nH]c1ccccc21
Yield: 66.4 %

Procedure:
To a solution of 4-amino-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester (6 g, 0.020 mol) in 50 mL THF was added 50 mL of H2O and paraformaldehyde (5 g) and the solution was heated at reflux for 2 hours under nitrogen. It was then cooled, concentrated in vacuo, and diluted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate solution, brine, dried and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane to give a white solid (4 g, 66.4% ) m.p. 86°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[N:23]([CH2:29][CH3:30])[C:22]=2[CH:31]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH:26]5[CH2:27][CH2:28]5)[N:23]([CH2:29][CH3:30])[C:22]=4[CH:31]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: CCn1c(C2CC2)nc2ccc(Br)cc21
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 120 °C
Yield: 47.7 %

Procedure:
The mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (100 mg), 6-bromo-2-cyclopropyl-1-ethyl-1H-benzimidazole (124 mg), copper iodide (81 mg), N,N′-dimethylethylenediamine (0.048 ml), potassium carbonate (147 mg) and DMSO (2.5 ml) was heated 120° C. for 1 h under microwave irradiation. The mixture was quenched with 28% NH3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc). The solid was recrystallized from IPA/hexane to give the title compound (85 mg) as a light pink solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Cl[C:42]1[CH:47]=[CH:46][N:45]=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]2)=[O:49])[CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][N:45]=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH3:56])[CH2:54][CH2:55]6)=[O:49])[CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CN1CCN(C(=O)c2cc(Cl)ccn2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(C(=O)N4CCN(C)CC4)c3)cn2)cc1
Yield: 96.4 %

Procedure:
Using 4-chloropicolinic acid chloride and N-methylpiperazine instead of N-Boc-piperazine, amidation was carried out in the same manner as Step A in Example 1-D-199, to obtain (4-chloro-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (215 mg, 0.398 mmol), and the obtained (4-chloro-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone (105 mg, 0.438 mmol) instead of 4-chloropicolinic acid t-butylamide, amination was carried out in the same manner as Example 1-D-07, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(4-methyl-piperazin-1-yl)-methanone as a yellow solid (285 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-200) as a yellow powder (69 mg, 38%).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[C:19]([NH2:22])(=[O:21])[CH3:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:22][C:19](=[O:21])[CH3:20])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1nccc2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 25 °C
Yield: 43.5 %

Procedure:
To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), acetamide (0.013 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified with reverse phase column chromatography, eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (25 mg, 44% yield). 1H NMR (500 MHz, DMSO-d6): δ 11.14 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 7.93 (d, J=5.5 Hz, 1H), 7.74-7.20 (m, 2H), 7.67-7.65 (m, 1H), 2.18 (s, 3H). LCMS (Method B): RT=5.02 min, m/z: 338.0 [M+H+].
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17].O>CS(C)=O>[Br:1][C:2]1[O:3][C:4]([C:7]([O:9][CH2:16][CH3:17])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(Br)o1
Reaction time: 15 h

Procedure:
To a solution of 2-bromo-5-carboxyfuran (10 g) in dimethyl sulfoxide (100 ml), potassium carbonate (7.96 g) was added at 15 to 30° C. and ethyl iodide (16.8 ml) was added dropwise thereto. The mixture was stirred for 15 hours. The reaction solution was then poured into water and extracted with chloroform. The organic layer was washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 11.34 g of the desired product as an oil.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[C:29]1([C:35]2[N:39]3[CH2:40][CH2:41][NH:42][CH2:43][C:38]3=[C:37]([C:44]([NH:46][CH:47]3[C:52]([CH3:54])([CH3:53])[CH:51]4[CH2:55][C:48]3([CH3:56])[CH2:49][CH2:50]4)=[O:45])[N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH:1]1([C:4]([N:42]2[CH2:41][CH2:40][N:39]3[C:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:36][C:37]([C:44]([NH:46][CH:47]4[C:52]([CH3:53])([CH3:54])[CH:51]5[CH2:55][C:48]4([CH3:56])[CH2:49][CH2:50]5)=[O:45])=[C:38]3[CH2:43]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC12CCC(C1)C(C)(C)C2NC(=O)c1nc(-c2ccccc2)n2c1CNCC2
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC12CCC(C1)C(C)(C)C2NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)C1CC1)CC2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of cyclopropanecarboxylic acid (1.2 eq.) in anhydrous DMF (2 mL) was distributed EDCI (1.6 eq.), HOBt (1.3 eq.) and TEA (5 eq.). The vial was sealed and stirred for 40 minutes at room temperature. Compound 39 (1 eq. in 1 mL of anhydrous DMF) was added to the vial which was then sealed and stirred overnight at room temperature. The solvent was removed by centrifugal evaporation under reduced pressure. The residue was dissolved in DCM (2 mL), and washed sequentially with 10% K2CO3 solution (1 mL) and water (1 mL). The water wash was then re-extracted with DCM (0.5 mL), the combined organic extracts were evaporated to dryness under reduced pressure. The desired product, Compound 119, was isolated by mass directed LC. LCMS (+ESI) m/z 447.38 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH2:14])[CH:6]=1)=[O:4].[Cl:15][C:16]1[N:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.ClCCl.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:22]([C:19]2[CH:20]=[N:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[O:23])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(=O)n(CCN)c1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(=O)n(CCNC(=O)c2ccc(Cl)nc2)c1
Temperature: -8 °C
Reaction time: 0.5 h

Procedure:
To a 1 00 ml round bottomed flask fitted with a magnetic stirrer bar and nitrogen inlet was added the above amine (0.300 g, 1.53 mmol), 6-chloro-3-pyridinecarboxylic acid (0.241 g, 1.53 mmol), and dry dichloromethane 125.5 mmol). Upon cooling in a -8° C. ice bath with stirring, triethyl amine (1.07 ml, 7.65 mmol) and propylphosphonic acid anhydride (0.50 ml, added as a 0.50 ml ethyl acetate solution, Angew. Chemie 1980, 92(2), 129) were added. The flask was allowed to warm slowly to room temperature over 1.25 hours. Stirring was continued 30 minutes at which time the reaction mixture solution was washed with aqueous sodium bicarbonate (2X), brine, and dried (Na2SO4). Filtration, concentration and purification via medium pressure liquid chromotography (silica gel, 4% methanol/dichloromethane) have the desired product, MP: 188°-190° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].S([O-])([O-])(=O)=O.[Mg+2]>[N+](C)([O-])=O.CCOCC.[Sc]>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Sc]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(C)=O)cc1
Temperature: 21 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
The catalytic effect of the scandium salt of 5-trifluoromethanesulfonyl-1,3-dibutyl-2-sulfonyl-barbituric acid, obtained in Example 25, towards a Friedel-Crafts reaction of acylation was evaluated in the following manner. In 40 ml of anhydrous nitromethane, there is added 887 mg (0.7 moles) of the scandium salt of 5-trifluoromethylsulfonyl-1,3-dibutyl-2-sulfonyl-barbituric acid, and 1.08 g (10 mmoles) of anisole and 2.04 g (20 mmoles) of acetic anhydride. After stirring during 10 min at 21° C., the reaction mixture was diluted with 50 ml of ether and the reaction was inhibited with 100 ml of a saturated solution of sodium bicarbonate NaHCO3. After filtration on Celite, the solution was extracted with three fractions of 50 ml ether, then the collected ether phase was washed with a saturated solution of potassium chloride. After drying the ether phase with magnesium sulfate and evaporation, 1.46 g of p-methoxyacetophenone (95% yield) were recovered with a purity characterized by a proton RMN higher than 99%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCCCCC
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
A 3 L 3-neck flask fitted with top stirrer, condenser and argon inlet/outlet was charged with 4-trifluoromethybenzene boronic acid (90.0 g, 0.474 mol), 4-bromobenzaldehyde (83.29 g, 0.450 mol) and 1,2-dimethoxyethane (1.3 L), followed by 2M aqueous sodium carbonate (474 ml) and palladium acetate (5.32 g, 0.0237 mol). The stirring mixture was heated to reflux for 4 h under argon, then allowed to cool to room temperature over 16 h. The reaction mixture was filtered through hyflo. The filtrate was diluted with saturated brine and extracted 3× with ethyl acetate. The combined extracts were dried over magnesium sulfate and filtered through hyflo, giving a clear orange filtrate which was evaporated to a solid (ca. 120 g, crude). Flash chromatography (silica, 10-50% dichloromethane in pet. ether, 10% steps) gave a white solid which dissolved in hexane (500 ml) on boiling. Crystallisation, finally in ice, gave the title compound as a solid which was filtered off, washed with ice cold hexane and dried, (86.33 g, 77%). 1H-NMR (CDCl3) δ 7.77-8.03 (8H, m), 10.09 (1H, s)
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][N:4]([CH:6]2[CH2:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[CH2:8][CH2:7]2)[CH2:3]1.[ClH:25]>CO>[ClH:25].[ClH:25].[F:24][C:2]1([F:1])[CH2:5][N:4]([CH:6]2[CH2:7][CH2:8][C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:22][CH2:23]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N3CC(F)(F)C3)CC2)CC1
Agent: Cl
Solvent: CO
Product: FC1(F)CN(C2CCC3(CCNCC3)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 9-(3,3-difluoroazetidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate (1.26 g, 3.66 mmol) was dissolved in hydrogen chloride in methanol (1.25 mol/l, 29 ml) and the solution was refluxed for 45 min. The solvent was removed in vacuo and the residue was dissolved in a small amount of ethanol. A solid was subsequently precipitated out by addition of acetone. The mixture was stirred at room temperature for 10 min, diethyl ether was then added and the mixture was stirred at room temperature for a further 30 min. The resulting precipitate was filtered out with suction, washed with diethyl ether and dried in vacuo. Yield: 1.1 g (95%)