Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:35])[NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[N:15]=[C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])[S:12][CH:13]=2)=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccccc3Cl)cc2)cs1)C(C)C
Reaction time: 16 h

Procedure:
To methyl-2-(4-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 3, 170 mg) in THF (2 ml), 2-chlorophenyl isocyanate (94 mg) was added and reaction mixture was stirred for 16 hours. Organic solvent was concentrated obtained sticky solid, was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain title compound as solid. Yield: 190 mg (76%). 1H NMR (DMSO-d6, 300 MHz): δ 9.58 (s, 1H), 8.80 (d, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.17 (d, 1H), 8.05 (d, 2H), 7.58 (d, 2H), 7.46 (d, 1H), 7.32 (t, 1H), 7.05 (t, 1H), 4.38 (t, 1H), 3.68 (s, 3H), 2.32 (m, 1H), 0.98 (t, 6H).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([C:11]2[S:10][C:9]3[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:8]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)c2sc3cc(OC)ccc3c2-c2ccccc2)cc1
Yield: 91 %

Procedure:
3-Phenyl-6-methoxybenzo[b]thiophene and 4-methoxybenzoyl chloride were converted to the title compound by the procedure of Example 1 in 91% yield, after crystallization from methanol.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:25]4[CH2:26][CH2:27][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:24]4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Yield: 90.5 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.28 g, 0.97 mmol) and tert-butyl piperazine-1-carboxylate (0.182 g, 0.97 mmol) according to the example 1, which was given tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)piperazine-1-carboxylate as a white solid (0.399 g, 90.0% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:40][C:41]1[C:42]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:43]=2[S:44][C:45]=1[C:46](Cl)=[O:47]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:46]([C:45]2[S:44][C:43]3[CH:49]=[CH:50][CH:51]=[C:52]([F:53])[C:42]=3[C:41]=2[Cl:40])=[O:47])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cccnc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccnc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
N3 is prepared according to a method similar to Method D. [4-(2-methoxy-5-pyridin-3-yl-benzylamino)-cyclohexyl]-carbamic acid tert-butyl ester (N2) (1.035 g, 2.52 mmol) is dissolved in 10 mL anhydrous methylene chloride. N,N-Diisopropylethylamine (0.526 mL, 3.02 mmol) is added followed by 3-chloro-4-fluoro-benzo[b]thiophene-2-carbonyl chloride (6) (0.690 g, 2.77 mmol). The mixture is allowed to stir overnight at room temperature and then is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and evaporated, and the residue is chromatographed on silica gel using a gradient elution of methanol/methylene chloride. {4-[(3-Chloro-4-fluoro-benzo[b]thiophene-2-carbonyl)-(2-methoxy-5-pyridin-3-yl-benzyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester (N3) is obtained (0.93 g, 1.48 mmol; 59% yield).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)OCC1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32](C2CCC(=O)CC2)[CH2:31][CH2:30]1>>[F:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:8]1[CH2:9][CH2:10][CH:5]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)[CH2:6][CH:7]=1
Reactant: Fc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Reactant: COc1ccccc1N1CCN(C2CCC(=O)CC2)CC1
Product: COc1ccccc1N1CCN(C2CC=C(c3c[nH]c4ccc(F)cc34)CC2)CC1

Procedure:
This compound was prepared in the manner described above for intermediate 1c b y replacing 1,4-cyclohexanedione monoethylene ketal with 4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexanone (1.44 g, 5 mmol). The crude mixture was used in next step without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:23])[CH:19]=[CH:20][C:21]#[N:22].C(N(CC)CC)C>O1CCOCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([C:20](=[CH:19][N:18]([CH3:23])[CH3:17])[C:21]#[N:22])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Reactant: CN(C)C=CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)C=C(C#N)C(=O)c1cccc(Oc2ccccc2)c1
Reaction time: 8 h
Yield: 36.2 %

Procedure:
A mixture of 3-phenoxybenzoyl chloride (6.9 g), 3-dimethylaminoacrylonitrile (2 g) and triethylamine (4 g) in dry dioxan (50 ml) was refluxed for 6 hours under a nitrogen atmosphere. After standing at room temperature overnight, the dioxan was evaporated in vacuo and dichloromethane added to the residue. The extracts were washed with water, 2N NaOH, brine and finally dried over MgSO4. After filtration and evaporation of the dichloromethane, the residue was purified on a silica gel column using 5% methanol-dichloromethane as eluant to give the title compound (2.2 g, 36%) as a white solid of m.p. 80°-82° C. (identical to that described in Example 46).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(C=O)s1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(C)s1)C(=O)OCC

Procedure:
A 215 g (1.71 moles) sample of 5-methyl-2-thiophenecarboxaldehyde, 258 ml (1.71 moles) diethyl malonate, 25 ml piperidine, 0.52 g benzoic acid, and 1.5 L toluene were placed into a round bottom flask and heated to reflux for four hr. with azeotropic removal of water. The reaction was cooled and water was added. The toluene layer was washed with sodium bicarbonate solution. 3N hydrochloric acid, water, brine and dried (MgSO4). The solvent was evaporated in vacuo. The residue was washed with methylcyclohexane. The washings were collected, the solvent removed in vacuo and the residue was recrystallized from methylcyclohexane. The solid materials were combined to give 299.86 g of diethyl 2-[(5-methyl-2-thienyl)methylene]propanedioate, mp 53°-56° C.
Reaction SMILES: [CH:1]1([C:7]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([N:21]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]#[C:24]CO)[CH3:20]>>[CH:12]1([C:7]([OH:18])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][C:24]#[C:23][CH2:22][N:21]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:19][CH3:20])=[O:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: CCN(CC#CCO)Cc1ccc(OC)cc1
Product: CCN(CC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1)Cc1ccc(OC)cc1

Procedure:
reacting methyl α-cyclohexyl-α-hydroxybenzeneacetate with 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butyn-1-ol in the presence of an anhydrous base to produce 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butynyl α-cyclohexyl-α-hydroxybenzeneacetate; and
Reaction SMILES: ClC(OCC(C)C)=O.[Cl:9][C:10]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13].C(N(CC)CC)C.[C:31]1([CH:37]([NH2:39])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH3:38][CH:37]([NH:39][C:16](=[O:18])[CH2:15][NH:14][C:12](=[O:13])[C:11]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:10]=1[Cl:9])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)CNC(=O)c1c(Cl)cccc1Cl
Reactant: CC(N)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(NC(=O)CNC(=O)c1c(Cl)cccc1Cl)c1ccccc1
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
1.05 g of isobutyl chloroformate was slowly dropped at -20° C. under a nitrogen stream onto a solution of 1.74 g of N-(2,6-dichlorobenzoyl)glycine and 0.71 g of triethylamine in 30 ml of anhydrous tetrahydrofuran, and the reaction solution was stirred for 20 minutes. Then, 0.84 g of α-phenylethylamine was added to the solution, which was subsequently stirred for 30 minutes keeping the reaction temperature within the range from -10° C. to -20° C. The reaction solution was then extracted with 60 ml of ethyl acetate. The extract was washed with a 10% w/v aqueous solution of sodium hydroxide, then with 1N aqueous hydrochloric acid, and finally with a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. The reaction solution was concentrated by evaporation under reduced pressure, and the resulting residue was subjected to silica gel column chromatography for purification to give 1.58 g (yield 67%) of the title product melting at 155° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[CH:4][C:3]=1[CH3:15].[OH-].[K+]>O1CCOCC1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[CH3:15]
Reactant: CCOC(=O)COc1ccc(F)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(OCC(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of ethyl 2-(4-fluoro-3-methylphenoxy)acetate (1.1 g, 5.1 mmol) in 10 mL dioxane was added 10 mL aqueous 5% KOH at 25° C. After being stirred for 30 min at room temperature the reaction was quenched by the addition of 12 mL of 1M aqueous HCl. The mixture was extracted ethyl acetate (2×40 mL) and the combined organic layers were washed with brine (2×30 mL). The solution was dried over Na2SO4 before being concentrated under reduced pressure. The crude product was used directly in the next reaction without further purification.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[OH:17]>C1(C)C=CC=CC=1>[CH:1]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[OH:17])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of isopropyl isocyanate (221 mg, 2.6 mmol) in toluene, 2-amino-5-nitrophenol (400 mg, 2.6 mmol) was added. The reaction mixture was stirred at 80° C. for 24 hours, then cooled to room temperature. The product was purified by precipitation from toluene and filtering (570 mg, 92%). m.p: 159.8-161.4° C.; EI-MS m/z 240 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5]S[CH2:3][CH2:2]1.O[O:18][S:19]([O-:21])=O.[K+]>CO.O>[N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3][S:19](=[O:21])(=[O:18])[CH2:5][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CCSCC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
To a solution of benzyl 4-thiomorpholinecarboxylate (4.8 g) in methanol (30 mL) and H2O (20 mL) was added oxone (16.2 g) under ice water cooling and the mixture was stirred at ambient temperature for 2 hours. The solution was evaporated in vacuo and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and EtOAc to give benzyl 4-thiomorpholinecarboxylate 1,1-dioxide as a colorless solid (3.8 g).
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH2:3][O:4][C:5](=[O:12])[NH:6][C:7]1[S:11][N:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37].CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C)C=O.O>[S:11]1[C:7]([N:6]([C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:13])[Cl:14])=[O:12])[C@H:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:8][CH:9]=[N:10]1
Reactant: O=C(Nc1ccns1)OCC(Cl)(Cl)Cl
Reactant: COC(=O)C(O)CC(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1ccns1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.2 %

Procedure:
A solution of 2,2,2-trichloroethylisothiazol-5-ylcarbamate (253 mg, 0.918 mmol), triphenylphosphine (266 mg, 1.01 mmol) and methyl 2-hydroxy-4-methylpentanoate (151 mg, 1.03 mmol) in N,N-dimethylformamide (2.0 mL) at 0° C. was treated dropwise with diisopropylazodicarboxylate (200 μL, 1.02 mmol) and stirred at rt for 5 h. The mixture was then poured into water and extracted with a 1:1 mixture of ether and ethyl acetate (3×). The combined organics were washed with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated. Flash chromatography of the residue on silica gel eluting with a mixture of ethyl acetate and, hexanes (1:3) gave 260 mg of methyl N-isothiazol-5-yl-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate as a faint-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)=[O:4].[NH:10]1[C:18]2[C:13](=[CH:14][C:15](B(O)O)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][CH:11]=[CH:12]3)[N:6]=1)=[O:4]
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1nc[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ncn(-c2ccc3[nH]ccc3c2)n1
Yield: 24.5 %

Procedure:
1H-1,2,4-triazole-3-carboxylic acid methyl ester (1.12 g, 8.79 mmol), 1H-indol-5-ylboronic acid (1.42 g, 8.79 mmol), N,N-dimethylformamide (90 mL), copper (II) acetate (1.20 g, 6.60 mmol) and pyridine (1.40 mL, 17.3 mmol) were reacted according to the same procedure as Preparation 1 to give the title compound (519.7 mg, 2.15 mmol, 24% Yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Li+].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][S:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:13][CH:12]=1)(=[O:16])=[O:15]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: O=S([O-])c1ccc(CN2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CN4CCOCC4)cc3)c(C)o2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of lithium 4-(morpholinomethyl)benzenesulfinate (2.0 g, 8.10 mmol, 1.43 equiv), methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (1.5 g, 5.66 mmol, 1.00 equiv) and potassium carbonate (780 mg, 5.65 mmol, 1.00 equiv) in N,N-dimethylformamide (60 mL) was stirred overnight at 70° C. The reaction mixture was cooled to room temperature and the product was precipitated by the addition of 150 mL of ice and water. The solid was collected by filtration, washed with 2×20 mL of water and dried in a vacuum oven to afford 1.5 g (57%) of methyl 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate as a white solid. LC-MS: (ES, m/z): 512 [M+CH3CN+H]+, 471 [M+H]+. 1HNMR (400 MHz, DMSO-d6, ppm) δ 8.04 (d, J=8.0Hz, 2H), 7.90 (d, J=8.0Hz, 2H), 7.72 (d, J=7.6Hz, 2H), 7.52 (d, J=7.6Hz, 2H), 4.67 (s, 2H), 3.88 (s, 3H), 3.55 (s, 6H), 3.31-3.29 (d, 4H), 2.32 (s, 4H), 2.15 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[CH:19]=[CH2:20].O>C1COCC1>[CH2:20]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[N:4][CH:5]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(C#N)nc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
4 mmol of 6-Cyanonicotinic acid were dissolved in THF. 1.5 eq. of Cs2CO3 were added he reaction stirred for 10 min. 1.5 eq allylbromide and a catalytic amount of KI were added he reaction heated to 100° C. for 4 h. The product was isolated via extraction from cetate/water.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:21]1[N:22]=[C:23]([C:30]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH3:42])[C:37](=[O:43])[N:36]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[C:35]3=[O:52])=[O:31])[N:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=12>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>[F:51][C:48]1[CH:49]=[CH:50][C:45]([CH2:44][N:36]2[C:35](=[O:52])[C:34]3[C:39](=[CH:40][CH:41]=[C:32]([C:30]([C:23]4[N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[C:21]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[N:22]=4)=[O:31])[CH:33]=3)[N:38]([CH3:42])[C:37]2=[O:43])=[CH:46][CH:47]=1
Reactant: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(-c4cccnc4)c4ccccn34)ccc21
Temperature: 150 °C
Yield: 87.9 %

Procedure:
0.04 g (0.32 mmol) of 3-pyridylboronic acid, 0.2 g (0.81 mmol) of potassium phosphate dihydrate dissolved in 0.29 ml of water, and 6.2 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added to 0.15 g (0.27 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)-1-methylquinazoline-2,4(1H,3H)-dione in 3 ml of DMF under an inert argon atmosphere. The reaction medium is microwave-heated at 150° C. for 20 minutes. After filtration over talc, the reaction medium is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 0.12 g of a yellow solid is obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([O:6][CH:7]1[CH2:8][CH2:9][CH:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)C1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.53 mL, 6.80 mmol) was added to a −20° C. solution of tert-butyl 4-hydroxycyclohexanecarboxylate (1.05 g, 5.25 mmol) and triethylamine (1.46 mL, 10.5 mmol) in dichloromethane (21 mL). The reaction was stirred for 2 hours, then saturated aqueous sodium bicarbonate was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 4-[(methylsulfonyl)oxy]cyclohexanecarboxylate. 1H NMR (500 MHz, CDCl3) δ 4.96-4.55 (m, 1H), 3.00 (s, 3H), 2.23-2.12 (m, 2H), 2.03-1.98 (m, 2H), 1.93-1.81 (m, 1H), 1.79-1.66 (m, 1H), 1.66-1.48 (m, 3H), 1.42 (s, 9H).
Reaction SMILES: [H][H].[F:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:8][C:7]([NH2:16])=[C:6]([N+:17]([O-])=O)[CH:5]=1>C(O)C.[Pd]>[F:3][C:4]1[CH:5]=[C:6]([NH2:17])[C:7]([NH2:16])=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: [H][H]
Reactant: COCCCOc1cc(N)c([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Product: COCCCOc1cc(N)c(N)cc1F
Yield: 100.2 %

Procedure:
In a 25 ml autoclave, dissolve 330 mg of 4-fluoro-5-(3-methoxypropoxy)-2-nitrophenylamine, obtained in the previous stage, in 20 ml of ethanol, add 40 mg of 10% palladium-on-charcoal and then subject to an initial hydrogen pressure of 1 bar at 20° C. for 16 hours. After cooling, the volume of hydrogen absorbed is 91 ml. After filtration of the catalyst and then concentration to dryness under reduced pressure, we obtain 290 mg of 4-fluoro-5-(3-methoxypropoxy)benzene-1,2-diamine, in the form of a viscous black oil, which is used as it is in the following stage, with the following characteristic: