Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: NC(=O)c1ccc(OCCCCl)cc1

Procedure:
A mixture composed of 0.004 mole of 4-hydroxybenzamide, 0.004 mole of 1-bromo-3-chloropropane and 0.006 mole of caesium carbonate in 10 ml of acetonitrile is heated at reflux for 5 hours.
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7](=[O:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[O:4].Cl.O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:15]([O:14][C:12]([C:11]1[CH:10]=[C:9]([NH:8][C:7](=[O:21])[NH:6][CH2:5][C:3]([OH:4])=[O:2])[CH:20]=[CH:19][CH:18]=1)=[O:13])[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)c1cccc(NC(=O)NCC(=O)OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)c1cccc(NC(=O)NCC(=O)O)c1
Reaction time: 2.5 h
Yield: 70.3 %

Procedure:
To a solution of allyl 3-(methoxycarbonylmethylureido)benzoate (5.27 g, 18.7 mmol) in THF (27 ml) is added 2N hydrochloric acid (37.4 ml), and the mixture is refluxed with stirring for 2.5 hours. After allowing to cool, water and an aqueous saturated sodium bicarbonate solution are added to the reaction solution to adjust the pH of the aqueous layer to 8, which is then extracted with ethyl acetate. Concentrated hydrochloric acid is added to the aqueous layer to adjust the pH to 1, followed by extraction with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is crystallized from toluene to obtain the objective compound (3.66 g). Yield 70%.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3].Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3]
Reactant: CN(C)CCCl
Reactant: NC(=O)Nc1cc(-c2cccc(O)c2)sc1C(N)=O
Product: CN(C)CCOc1cccc(-c2cc(NC(N)=O)c(C(N)=O)s2)c1

Procedure:
Prepared by the method of Example 9(b) using the product of Example 6 and N-(2-chloroethyl)dimethylamine.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:12])=O>>[CH:1]1([CH2:6][C:7]([Cl:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC1CCCC1
Yield: 81 %

Procedure:
Cyclopentane acetic acid (17 g, 0.132mole) was stirred into 50 mls of thionyl chloride and refluxed for two hours. The mixture was cooled and the excess solvent was removed via distillation at atmospheric pressure. The residue was distilled (b.p.=38°-39° C. at 0.1 mm Hg) to give 15 g of the title compound (81% distilled yield).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:21]([C:26]4[CH:27]=[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([O:41]C)=[O:40])=[CH:35][C:34]=5[CH3:43])[CH:29]=[CH:30][C:31]=4[F:32])=[N:22][CH:23]=[CH:24][N:25]=3)[C@H:14]2[CH3:44])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].O.Cl>O1CCOCC1>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:21]([C:26]4[CH:27]=[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([OH:41])=[O:40])=[CH:35][C:34]=5[CH3:43])[CH:29]=[CH:30][C:31]=4[F:32])=[N:22][CH:23]=[CH:24][N:25]=3)[C@H:14]2[CH3:44])[CH:4]=[C:3]([C:2]([F:1])([F:46])[F:45])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)c(-c3nccnc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1-c1ccc(F)c(-c2nccnc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
Methyl 3′-[3-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrazin-2-yl]-4′-fluoro-2-methylbiphenyl-4-carboxylate (Step F, 16 mg, 0.025 mmol) and lithium hydroxide monohydrate (5.18 mg, 0.124 mmol) were stirred in 1,4-dioxane (0.914 mL)/water (0.571 mL) at room temperature for 2 days. Crude mixture was acidified with HCl (1N) and purified by preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with MeCN/water+0.1% TFA (10% to 100% organic in 10 min, hold 100% in 2 min, 20 mL/min). Related fractions were pooled and evaporated in vacuo to afford an aqueous mixture. The resulting aqueous mixture was extracted with EtOAc, washed with water and then with brine, dried (Na2SO4), filtered and concentrated to afford a colorless glass as the titled compound. LCMS calc. 633.15=; found=634.25 (M+H)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 8.70 (d, J=2.5 Hz, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.01 (s, 1H), 7.95 (dd, J=8, 1.5 Hz, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.51-7.46 (m, 2H), 7.37 (d, J=8 Hz, 1H), 7.31 (t, J=8 Hz, 1H), 5.74 (d, J=8.5 Hz, 1H), 4.95 (d, J=17 Hz, 1H), 4.44-4.36 (m, 2H), 2.37 (s, 3H), 0.77 (d, J=6 Hz, 3H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:11])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH:21]([C:26](O)=O)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>O1CCOCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH:21]([C:26]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=3)[N:11]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: N=C(NO)c1ccc(F)cc1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Yield: 17.5 %

Procedure:
A mixture of N-hydroxy-4-fluoro-benzamidine (0.758 g, 4.92 mmol), 4-methyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (4.92 mmol), prepared as described in 62(B), EDCI.HCl (1.41 g, 7.38 mmol), HOBT (0.665 g, 4.92 mmol) and anhydrous triethylamine (1.38 mL, 9.84 mmol) in dioxane (80 mL) was stirred at room temperature for a week-end, under nitrogen atmosphere. Then, the reaction mixture was refluxed for 7 h and the solvent was evaporated under reduced pressure. The residue was diluted with water (50 mL) and ethyl acetate (50 mL), the phases were separated and the organic layer was washed sequentially with water (50 mL×2 times) and with NaOH 1N (50 mL×2 times). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil. Purification of the crude by flash chromatography (silica gel, eluent gradient: from hexane/ethyl acetate 8/2 to hexane/ethyl acetate 7/3) afforded 0.312 g of 3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH2:23][CH3:24])[C:16](=[O:22])[N:17]([CH2:20][CH3:21])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[CH3:27][O:28][CH2:29][CH2:30][C:31]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH2:20]([N:17]1[C:18]([CH3:19])=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C@@H:4]([C:3]([OH:2])=[O:26])[NH:5][C:36]([C:31]3([CH2:30][CH2:29][O:28][CH3:27])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:37])=[CH:8][CH:9]=2)[C:14](=[O:25])[N:15]([CH2:23][CH3:24])[C:16]1=[O:22])[CH3:21]
Reactant: CCn1c(C)c(-c2ccc(C[C@H](N)C(=O)OC)cc2)c(=O)n(CC)c1=O
Reactant: COCCC1(C(=O)O)CCCC1
Product: CCn1c(C)c(-c2ccc(C[C@H](NC(=O)C3(CCOC)CCCC3)C(=O)O)cc2)c(=O)n(CC)c1=O

Procedure:
4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine was prepared from 4-(1, 3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 1-(2-methoxyethyl)cyclopentane carboxylic acid using the general procedures described in example 19 and was obtained as an amorphous white solid. ES-HRMS m/e calcd for C27H37N3O6 (M+Na) 522.2575, found 522.2581.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:13][CH3:14])(=[O:12])[CH2:10][CH3:11].[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH3:14][O:13][C:9](=[O:12])[CH:10]([CH3:11])[CH:27]([C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)[OH:28]
Reactant: CCC(=O)OC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
LDA (1.3 mL, 2.6 mmol) was added to a solution of methyl propionate (0.22 g, 2.6 mmol) in THF (5 mL) cooled to −78° C. under nitrogen atmosphere. The reaction was stirred for 30 min, and then 4-benzyloxy-benzaldehyde (0.50 g, 2.4 mmol) in THF (5 mL) was added. The reaction was stirred at −78° C. for 5 min, and then allowed to warm to room temperature and stirred overnight. The reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by FCC on silica gel eluting ethyl acetate:hexane (15:85 to 25:75) gradient to give 3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-propionic acid methyl ester (0.12 g, 16%) as an oil. MS found: (M+H)+=301.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]4[C@@H:25]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)[CH2:24][N:23]([C@@:33]([CH:47]5[CH2:50][CH2:49][CH2:48]5)([CH3:46])[C:34]([O:36]CC5C=CC(OC)=CC=5)=[O:35])[CH2:22]4)[CH2:16][CH2:15]3)=[CH:12][N:13]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[C:1]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][C@@H:21]4[C@@H:25]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)[CH2:24][N:23]([C@@:33]([CH:47]5[CH2:48][CH2:49][CH2:50]5)([CH3:46])[C:34]([OH:36])=[O:35])[CH2:22]4)[CH2:18][CH2:19]3)=[CH:12][N:13]=[C:7]2[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(COC(=O)[C@@](C)(C2CCC2)N2C[C@H](CN3CCC(c4cnc5cc(C(C)(C)C)ccn45)CC3)[C@@H](c3cccc(F)c3)C2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccn2c(C3CCN(C[C@H]4CN([C@@](C)(C(=O)O)C5CCC5)C[C@@H]4c4cccc(F)c4)CC3)cnc2c1
Yield: 91.1 %

Procedure:
The title compound was prepared from 40 mg of α-(R)-(3-(S)-((4-(7-t-butyl-imidazo[1,2-a]pyridin-3-yl)-piperidine-1-yl)methyl)-4-(S)-(3-fluorophenyl) pyrrolidin-1-yl)-cyclobutylpropanoic acid, 4-methoxy-benzyl ester (from Step D), 2 mL of TFA and 0.4 mL of anisole, using a procedure analogous to that described in Example 235, Step D to provide 30 mg of the title compound as a foamy solid. ESI-MS 561 (M+H); HPLC A 1.92 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>>[CH2:27]([O:6][C:5](=[O:7])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([F:18])([F:19])[F:20])[CH:9]=1)[CH2:3][CH:2]([CH3:21])[CH3:1])[CH3:28]
Reactant: CCO
Reactant: CC(C)CC(C(=O)O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CC(C)C)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 83 %

Procedure:
To a solution of 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid (42.3 g, 139 mmol) in absolute ethanol (300 mL) was added concentrated sulfuric acid (95-98%, 9.0 mL) and the solution was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure; the residue was treated with a solution of sodium carbonate (5%, 300 mL) and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification by silica-gel flash chromatography eluting with heptane/EtOAc (10:1) gave 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester (38.4 g, 83%) as a yellowish oil: 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H, J=8.4 Hz), 7.82 (s, 1H), 7.74 (dd, 1H, J=8.4, 1.5 Hz), 4.18 (m, 2H), 3.83 (t, 1H, J=7.5 Hz), 2.06 (m, 1H), 1.70 (m, 1H), 1.50 (m, 1H), 1.27 (t, 3H, J=7.2 Hz), 0.97 (d, 3H, J=6.6 Hz), 0.96 (d, 3H, J=6.3 Hz); 13C NMR (75 MHz, CDCl3): δ 172.24, 146.83, 145.04, 132.40, 127.51 (q, J=5 Hz), 125.28, 123.80 (q, J=32 Hz), 121.78 (q, J=272 Hz), 61.45, 49.45, 42.65, 26.03, 22.41, 22.17, 14.10.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH3:13])[CH:9]=[C:8]([C:14]([OH:16])=[O:15])[C:7]2=[O:17].[NH2:19][CH:20]1[CH:28]=[CH:27][CH:26]([CH3:29])[CH:25]2[CH:21]1[CH2:22][NH:23][CH2:24]2.N12CCN(CC1)CC2>CS(C)=O>[NH2:19][CH:20]1[CH:28]=[CH:27][CH:26]([CH3:29])[CH:25]2[CH:21]1[CH2:22][N:23]([C:3]1[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:17])[C:8]([C:14]([OH:16])=[O:15])=[CH:9][N:10]3[CH2:12][CH3:13])=[CH:5][CH:4]=1)[CH2:24]2
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(F)c(Cl)c21
Reactant: CC1C=CC(N)C2CNCC12
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(N3CC4C(C)C=CC(N)C4C3)c(Cl)c21

Procedure:
270 mg (1 mmol) of 8-chloro-1-ethyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid together with 180 mg (1.2 mmol) of 4-amino-7-methyl-1,3,3a,4,7,7a-hexahydroisoindole and 224 mg (2 mmol) of 1,4-diazabicyclo[2.2.2]octane are heated for three hours at 100° C. in 10 ml of dimethyl sulphoxide.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH:10]=[C:11]([CH3:25])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:24])[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)C(OC)=O)(=[O:3])[CH3:2].[Cl-].[Na+].O>CS(C)=O>[CH3:25][C:11]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:24])[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)=[CH:10][CH2:9][CH2:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)C(CC=C(C)CCC=C(C)COC1CCCCO1)C(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)CCC=C(C)CCC=C(C)COC1CCCCO1
Temperature: 150 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of methyl 2-acetyl-5,9-dimethyl-10-(2-tetrahydropyranyl)oxy-4,8-decadienate (370 mg, 1.05 mmol) in methylsulfoxide (2 ml) were added sodium chloride (180 mg, 3.08 mmol) and water (0.1 ml), and the mixture was stirred at 150° C. After four hours, the reaction mixture was allowed to cool to room temperature, and water (15 ml) was added thereto. The product was extracted with ether (20 mlx2). The extract was dried over Na2SO4, and concentrated to give a residue, which was then purified with silica gel column chromatography to obtain 6,10-dimethyl-11-(2-tetrahydropyranyl)oxy-5,9-undecadien-2-one (70%). IR(film)cm-1 ; 2950, 2880, 1720, 1442, 1358, 1120, 1078, 1024, 905, 870, 815.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[CH:7][NH:6][C:5]=2[C:9]([OH:11])=O)[CH2:3][CH2:2]1.[C:12](Cl)(=O)[C:13](Cl)=O>ClCCl.CN(C)C=O>[CH:1]1([C:4]2[CH:8]=[CH:7][NH:6][C:5]=2[C:9]([NH:6][C:5]2[CH:4]=[CH:1][CH:2]=[CH:3][C:12]=2[CH3:13])=[O:11])[CH2:2][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1[nH]ccc1C1CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1[nH]ccc1C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 186.6 %

Procedure:
To a suspension of the 3-cyclopropyl-1H-pyrrole-2-carboxylic acid (50 mg, 0,33 mmol) in dry dichloromethane (0.4 mL) was added a solution of oxalyl chloride (0.04 mL, 0,37 mmol) in 0.3 mL of dichloromethane atroom temperatureand 3 drops of N,N-dimethylformamide. After 1.5 h at this temperature, the mixture was concentrated under vacuum and the residue was redissolved in dichloromethane (1 mL). To this solution was added a solution of o-toluidine in dichloromethane (0,2 mL) and the mixture was stirred at room temperature overnight. The reaction was worked-up diluting with dichloromethane and washing with sodium bicarbonate (2×) and brine. The organic phase was dried and concentrated to give 74 mg of the title compound (88% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:26](O)[C:27]#[C:28][CH3:29]>>[CH2:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)[C:27]#[C:28][CH3:29]
Reactant: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(-c2cccs2)cc1
Reactant: CC#CCO
Product: CC#CCOc1ccc(SC(C(=O)OCC)c2ccc(-c3cccs3)cc2)cc1
Yield: 74 %

Procedure:
Ethyl {[4-(2-butynyloxy)phenyl]sulfanyl}[4-(2-thienyl)phenyl]acetate was prepared according to the general method as outlined in example 83 (step 2), starting from ethyl [(4-hydroxyphenyl)sulfanyl][4-(2-thienyl)phenyl]acetate (1.6 g, 4.3 mmol) and 2-butyn-1-ol (0.33 ml, 4.32 mmol); 1.34 g yellow oil. Yield 74%; MS(EI): 421.71 (M+H)+
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[C:12]([CH3:24])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.N>CO.[Pd]>[NH:1]([C:8]1[N:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]2[N:11]=[C:12]([CH3:24])[C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:14][C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(cc1/C=C/C(=O)O)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O=CO
Product: Cc1nc2c(cc1CCC(=O)O)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Yield: 86.4 %

Procedure:
To a stirred suspension of 2-anilino-6-[(E)-3-hydroxy-3-oxo-1-propenyl]-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (40.0 mg, 0.100 mmol) in MeOH (2.0 mL), was added Pd/C (5.3 mg, 10% weight on carbon) under an argon atmosphere, followed by the addition of ammonia formate (19.0 mg, 0.30 mmol) in a single portion. The reaction mixture was heated at reflux for 2 h, cooled and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was washed with water and dried in vacuo to afford 3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)propanoicacid (34.5 mg, 86%): LCMS RT: 2.31 min, MH+: 400.4, Rf=0.61 (4:1 EtOAc:MeOH).
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[S:20][CH2:21][C@@H:22]([C:31]([OH:33])=O)[NH:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].CN(C=O)C>CCOC(C)=O>[CH3:27][C:26]([CH3:29])([CH3:28])[C:25]([O:24][NH:23][C@@H:22]1[C:31](=[O:33])[NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[S:20][CH2:21]1)=[O:30]
Reactant: COc1cccc(SC[C@H](NOC(=O)C(C)(C)C)C(=O)O)c1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc2c1NC(=O)[C@@H](NOC(=O)C(C)(C)C)CS2
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
0.948 mL of diethyl cyanophosphonate (1.019 g, 6.245 mmol) is placed in a 100 mL three-necked flask containing 1.80 g of 54 (5.26 mmol) and 25 mL of DMF, at 0° C., followed by addition, after 10 minutes, of 0.708 mL of TEA (5.04 mmol). The reaction medium is stirred at 0° C. for 2 hours. 50 mL of EtOAc are added and the mixture is then washed with twice 50 mL of distilled water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. The crude product is chromatographed on a silica cartridge (150 g) eluting with heptane/EtOAc (as an EtOAc gradient: 10% to 50%). 450 mg of expected product 55 are obtained (white solid).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[CH:12]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](C)([O-])=O>[CH:12]1([C:17]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=3[C:7]=2[CH3:10])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1coc2ccc(F)cc12
Reactant: O=C(Cl)C1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cc1c(C(=O)C2CCCC2)oc2ccc(F)cc12
Reaction time: 3 h
Yield: 64.3 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran (2.0 g) synthesized above, cyclopentanecarbonylchloride (1.94 g) in nitromethane (40 mL) was added aluminum chloride (anhydrous) (2.66 g) at 0° C., and the mixture was stirred for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-95:5, v/v) to give the title compound (2.11 g, 64%) as a colorless amorphous form.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:32])[CH:29]([CH3:31])[CH3:30]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC(C)C(=O)O
Agent: Cl
Product: CC(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (62 mg, 62%), MS (ISP) m/z=401.5 [(M+H)+], mp 219° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and isobutyric acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]([CH2:26][CH3:27])[CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1>>[CH2:26]([N:14]([CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]1[N:3]=[C:2]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[N:5]=1)[CH3:27]
Reactant: CCN(CCc1c[nH]c2ccccc12)c1nc(Cl)cc(N2CCCCC2)n1
Reactant: Cc1ccc(N)cc1
Product: CCN(CCc1c[nH]c2ccccc12)c1nc(Nc2ccc(C)cc2)cc(N2CCCCC2)n1
Temperature: 160 °C

Procedure:
A mixture of N-[4-chloro-6-(1-piperidinyl)-2-pyrimidinyl]-N-ethyl-N-[2-(1H-indol-3-yl)ethyl]amine (33.4 mg, 0.087 mmol) and p-toluidine (47 mg, 0.43 mmol) was heated neat under argon at 160° C. in a sealed tube for 12 hours. The crude material was purified by preparative TLC, eluting with hexane/ethyl acetate (4:1). N2-Ethyl-N2-[2-(1H-3-indolyl)ethyl]-N4-(4-methylphenyl)-6-piperidino-2,4-pyrimidinediamine was obtained, from a band at Rf=0.37, as a solid (15 mg, 0.033 mmol, 38%).
Reaction SMILES: [F:1][C:2]([F:8])=[C:3]([CH3:7])[CH2:4][CH2:5][OH:6].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>O1CCCC1>[CH3:9][S:10]([O:6][CH2:5][CH2:4][C:3]([CH3:7])=[C:2]([F:8])[F:1])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CCO)=C(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CCOS(C)(=O)=O)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To 100 ml of tetrahydrofuran, 4.45 g (36 mmol) of 4,4-difluoro-3-methyl-3-butenol and 4.59 g (40 mmol) of methanesulfonyl chloride were dissolved, followed by drop-wisely adding 4.42 g (44 mmol) of triethylamine under ice-cooling. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature for 1 hour. Hydrochloric acid salt of triethylamine was filtered, followed by adding water to the filtrate and extracting with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 7.20 g (yield: 99%) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate.