Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH:32]=[C:33]([O:35][CH2:36][CH3:37])[CH:34]=1)[O:18][CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[CH2:36]([O:35][C:33]1[CH:34]=[C:15]([CH:16]=[C:17]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH:32]=1)[CH2:14][S:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1)[CH3:37]
Reactant: CCOc1cc(CCl)cc(OCc2nc(-c3ccccc3)oc2C)c1
Reactant: COC(=O)Cc1sc(S)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(CSc2nc(C)c(CC(=O)OC)s2)cc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of methyl (2-mercapto-4-methylthiazol-5-yl)acetate (455 mg), 4-(3-chloromethyl-5-ethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (800 mg), potassium carbonate (465 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [2-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]-4-methylthiazol-5-yl]acetate (1.02 g, yield 87%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([O:9][CH:10](OCC)OCC)[CH3:8]>>[CH2:7]([O:9][CH:10]1[O:5][CH:2]([CH2:3][OH:4])[CH2:1][O:6]1)[CH3:8]
Reactant: OCC(O)CO
Reactant: CCOC(OCC)OCC
Product: CCOC1OCC(CO)O1

Procedure:
To 59.72 grams (0.655 moles) of anhydrous 1,2,3-propanetriol in a 500 milliliter 3-necked borosilicate flask equipped with a stirrer, a nitrogen inlet and a Vigreaux column, was added with constant stirring under a nitrogen atmosphere 97.9 (0.660 moles) of anhydrous triethylorthoformate and the reactants permitted to react for 6 hours. The reaction was carried out at atmospheric pressure, and at 130° C. ± 2° C. During the reaction, approximately a stoichiometric amount of ethanol was distilled from the reaction vessel. Next, the product was transferred to a 250 milliliter Bantam flask for vacuum fractionation over CaO, with the main fraction collected at 67°-85° C. under 0.5 millimeters of mercury. The fraction as analyzed by gas chromatography had a purity of 90% and it contained both the cis and trans isomers. An infrared analysis did not show any carbonyl peaks. Finally, the product was redistilled from triethylamine to yield pure monomer, 2-ethoxy-4-hydroxymethyl-1,3-dioxolane.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)cc1-c1ccc(Cl)cc1

Procedure:
134 mg (90%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(3,4-dichlorophenyl)piperazine (64 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: C([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:12]=1[O:25][CH3:26])([CH2:9][CH3:10])[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>C(O)C.O>[CH3:26][O:25][C:12]1[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:15]=[CH:16][C:11]=1[CH:3]([CH2:9][CH3:10])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C#N)(CC)c1cccc(Oc2ccccc2Cl)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C(=O)O)c1cccc(Oc2ccccc2Cl)c1OC
Yield: 82 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]butyrate (5.9 g) and potassium hydroxide (4.5 g) in ethanol (80 ml) and water (40 ml) was treated in a similar manner to that of Example 14-(7). The resultant residue was washed with n-hexane and dried to give 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]butyric acid (4.15 g).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)([CH:13]=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].O.O.P([O-])(O)(O)=[O:24].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH:15]1([C:11]2([C:13]([OH:24])=[O:14])[CH2:12][CH:7]3[CH2:6][N:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[CH2:9][CH:8]3[CH2:10]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CN(C)C(=O)N1CC2CC(C=O)(C3CCCC3)CC2C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC2CC(C(=O)O)(C3CCCC3)CC2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
5-Cyclopentyl-5-formyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 16b (0.266 g, 0.955 mmol) was dissolved in a solvent mixture of 20 mL of tetrahydrofuran and 10 mL of water. Then sodium dihydrogenphosphate dihydrate (0.448 g, 2.87 mmol), sodium chlorite (0.26 g, 2.87 mmol) and 2-methyl-2-butene (0.24 mL, 2.88 mmol) were added at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated to remove tetrahydrofuran and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyclopentyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 16c (0.28 g, yield 99.6%) as a yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>O.CN(C)C(=O)C>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 150 °C
Yield: 90 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in an oven-dried flask with 3-(S)-amino-3-o-tolyl-propionic acid (84 mg, 0.468 mmol) (commercially available from Combi-Blocks SS-1801) and N,N-dimethylacetamide (1.5 mL) was added with stirring. Solid sodium methoxide (25 mg, 0.468 mmol) was added and the reaction was heated to 150° C. in an oil bath for approximately five hours. The reaction was cooled and the solution diluted with five volumes of water. The solution was acidified to pH 3 with 1M hydrochloric acid to induce precipitation. Filtration of the solid followed by vacuum drying provided the desired product in 90% yield. LC-MS ESI−: 466 (M−1)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH:9]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]2)[N:5]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=2[F:26])[N:3]=1.[N:27]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28]1.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]>[F:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:17][C:4]1[N:3]=[C:2]([NH:34][S:31]([N:27]2[CH2:30][CH2:29][CH2:28]2)(=[O:33])=[O:32])[CH:7]=[C:6]([CH2:8][CH:9]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]2)[N:5]=1
Reactant: CC1(C)OCC(Cc2cc(Cl)nc(SCc3cccc(F)c3F)n2)CO1
Reactant: NS(=O)(=O)N1CCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)OCC(Cc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)CO1

Procedure:
A solution of the product of step i) (109 mg), tris(dibenzylideneacetone)dipalladium(0) (14 mg), azetidine-1-sulphonamide (145 mg), 2-dicyclohexyl-phosphino-2′,4′,6′-tri-isopropyl,1,1′-biphenyl (XPHOS)(14 mg) and cesium carbonate (120 mg) in anhydrous dioxane (2.3 ml) was heated at 100° C. for 45 min. The reaction mixture was partitioned between ethyl acetate and water. Acetic acid (0.2 ml) was added and the separated organic phase was washed with water and brine, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash silica-gel chromatography eluting with 40% ethyl acetate in iso-hexane to give the sub-title compound as a yellow viscous oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH3:30][C:31]1[CH:35]=[CH:34][NH:33][N:32]=1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:33]2[CH:34]=[CH:35][C:31]([CH3:30])=[N:32]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1cc[nH]n1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Product: Cc1ccn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)n1

Procedure:
The title compound was prepared according to the procedure described for example 294 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and 3-Methyl-1H-pyrazole (15%yield, white solid, MS (m/e): 493.5 (M+H, 100%)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:11]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][OH:2])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCOc1ccccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccccc1CO
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The title compound is prepared by the procedure of Example 19 using 20.0 g of product from Example 17, 200 ml of dry tetrahydrofuran and 6.53 g of lithium aluminum hydride. The reaction is stirred at room temperature for 60 hours. The product, 18.4 g, is obtained as colorless crystals.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:49][C:50]1[CH:51]=[C:52]([S:57](Cl)(=[O:59])=[O:58])[CH:53]=[C:54]([Cl:56])[CH:55]=1>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:57]([C:52]1[CH:51]=[C:50]([Cl:49])[CH:55]=[C:54]([Cl:56])[CH:53]=1)(=[O:59])=[O:58])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3cc(Cl)cc(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 60 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added 3,5-dichlorobenzenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 60% yield.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[C-:20]#[N:21].[K+].S([O-])(O)=O.[Na+].O>O1CCCC1>[C:20]([CH:15]([OH:16])[C:12]1[CH:11]=[CH:10][C:9]([C:7]2[NH:8][C:4]3[CH:3]=[C:2]([Cl:1])[C:18]([Cl:19])=[CH:17][C:5]=3[N:6]=2)=[CH:14][CH:13]=1)#[N:21]
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.4 %

Procedure:
To a solution of 5,6-dichloro-2-(4-formylphenyl)benzimidazole (291 mg, 1.00 mmol) in tetrahydrofuran (40 mL) were added potassium cyanide (260 mg, 4.00 mmol), sodium hydrogen sulfite (500 mg), and water (10 mL). The mixture was stirred at room temperature for 12 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 2-[4-[cyano(hydroxy)methyl]phenyl]-5,6-dichlorobenzimidazole (278 mg, 87%).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5].[SH:15][CH2:16][CH2:17][CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:21]([O:20][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[CH2:18][CH2:17][CH2:16][S:15][CH:2]([CH3:1])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5])[CH3:22]
Reactant: CCO[Si](CCCS)(OCC)OCC
Reactant: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCO[Si](CCCSC(C)CC(=O)C1C(C)=CCCC1(C)C)(OCC)OCC
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
A solution of α-damascone (9.60 g; 50.0 mmol) and 3-mercaptopropyltriethoxysilane (95% pure, 12.52 g, 50.0 mmol) in THF (40 ml) was treated with DBU (1.52 g, 10.0 mmol) and stirred at 40° C. for 90 min. The reaction solution was treated with 5% HCl, extracted twice with ether, washed with water, saturated aqueous NaHCO3 and then with saturated aqueous NaCl, dried over Na2SO4 and concentrated at 70° C./0.01 mbar. The reaction yielded 21.2 g (99%). of crude product:
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1)[C:4]([NH2:6])=[NH:5].CS([C:20]1[NH:21][CH:22]=[C:23]([CH3:28])[C:24]=1[N+:25]([O-:27])=[O:26])=O>>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:20]2[NH:21][CH:22]=[C:23]([CH3:28])[C:24]=2[N+:25]([O-:27])=[O:26])[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: Cc1c[nH]c(S(C)=O)c1[N+](=O)[O-]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Product: Cc1c[nH]c(NCCSCc2csc(NC(=N)N)n2)c1[N+](=O)[O-]

Procedure:
The title compound is prepared from 2-(2-Guanidino-4-thiazolylmethylthio)-ethylamine dihydrochloride and 2-methylsulphinyl-4-methyl-3-nitropyrrole by a process analogous to that described in Example 1.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:9]1([CH:15]([OH:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:1]([O:17][CH:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:16])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(O)c1ccccc1
Reactant: COC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC(C)c1ccccc1
Temperature: 110 °C
Yield: 97 %

Procedure:
In this example, procedure of transestrification of methyl acetoacetate with 1-phenyl ethanol is described. A mixture of 1 equivalent of methyl acetoacetate, 1 equivalent of 1-phenyl ethanol and 100 mg of sulfated tin oxide catalyst in 20 ml of toluene was heated to 110° C. in a two necked round bottom flask provided with a distillation condenser to remove methanol. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction (about 6 hours), the catalyst was filtered and the filtrate was concentrated and chromatographed on a silica gel column (95% petroleum ether and 5% ethyl acetate) to afford 1-phenylethyl acetoacetate as a viscous colorless liquid in 97% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17]([C:20]4[O:24][N:23]=[C:22]([C:25](OCC)=[O:26])[CH:21]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].[NH4+].[Cl-].C[N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CO.CN(C=O)C>[F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17]([C:20]4[O:24][N:23]=[C:22]([C:25]([NH2:35])=[O:26])[CH:21]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)on1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)on1
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a solution of ethyl 5-(6((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)isoxazole-3-carboxylate (200 mg, 0.40 mmol) in THF/MeOH mixture (12 mL, 5:1) was added LiOH (1M, 1.2 mL) at rt. The reaction mixture was stirred overnight and concentrated. To this crude mixture was added NH4Cl (60 mg, 1.2 mmol), HBTU (246 mg, 0.65 mmol), DIEA (132 uL, 0.8 mmol), and DMF (5.0 mL). The mixture was stirred at rt overnight, filtered, and purified by reverse phase chromatography to provide the title compound as a white solid (23.2 mg, 16%), LRMS (M+H+) m/z 369.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([NH:24]C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:12][CH2:13]2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCN(C(=O)OCc3ccccc3)CC2)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCN(CC2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.2 %

Procedure:
To a solution of 1-(1-benzyloxycarbonyl-4-piperidinylmethyl)-4-(t-butoxycarbonylamino)piperidine (7.77 g) in ethanol (30 ml) is added a 30% solution of hydrochloric acid in ethanol (15 ml) under ice-cooling, and the mixture is stirred at room temperature for 5 hours. The solvent is evaporated under reduced pressure, and the residue is dissolved in water. The solution is basified with potassium carbonate and extracted with chloroform. The extract is washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure to give the desired compound (6.04 g) as an oily product.
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2Cl)=[O:6].[C:18]1([S:24]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[NH:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])=[CH:32][CH:31]=1)=[O:6]
Reactant: COCNC(=O)c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COCNC(=O)c1ccc2ncnc(Nc3ccc(S(=O)(=O)c4ccccc4)cc3)c2c1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
4-Chloroquinazoline-6-carboxylic acid methoxymethylamide (XIV-1, 550 rag), 611 mg of 4-benzenesulfonylphenylamine, 49 mg of palladium (II) acetate, 190 mg of Xant phos and 997 mg of cesium carbonate were added to 1,4-dioxane (30 ml), and the interior of a reaction vessel was replaced with a nitrogen gas, followed by stirring at 100° C. for 2.5 hours. The reaction mixture was filtrated with Celite, and water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over sodium sulfate. The filtrated was concentrated, and the residue was purified by silica gel column chromatography (eluting with ethyl acetate:methanol=95:5) to obtain 4-(4-benzenesulfonylphenylamino)-quinazoline-6-carboxylic acid methoxymethylamide (XI-3, 651 tag) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([C:4](=[O:16])[C:5]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)=[C:6]([S:9][CH3:10])[S:7][CH3:8])[CH3:3].[BH4-].[Na+]>CO>[CH3:3][C:2]([CH3:17])([CH:4]([OH:16])[C:5]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)=[C:6]([S:7][CH3:8])[S:9][CH3:10])[CH3:1]
Reactant: CSC(SC)=C(C(=O)C(C)(C)C)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CSC(SC)=C(C(O)C(C)(C)C)n1cncn1
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
15 g (0.055 mol) of 2,2-dimethyl-5,5-dimethylthio-4-(1,2,4-triazol-1-yl)-pent-4-en-3-one (obtained as described in Example 1) were dissolved in 100 ml of methanol, and 2.1 g (0.055 mol) of sodium borohydride were added at room temperature. The mixture was stirred for a further 30 minutes at 20° to 30° C., and was concentrated. The residue was partitioned between methylene chloride and water. The organic phase was separated off, dried over sodium sulphate and concentrated. 11.9 g (80% of theory) of 2,2-dimethyl-5,5-dimethylthio-4-(1,2,4-triazol-1-yl)-pent-4-en-3-ol of melting point 108° to 111° C. were obtained.
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:1][CH:2]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:35][CH:34]=1
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(OC)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenol: ESMS m/e: 517.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:10]([O:12]C)=[O:11])[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:9])[F:8].[OH-].[Na+].Cl>O>[CH3:1][C:2]1([C:10]([OH:12])=[O:11])[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:9])[F:8]
Reactant: COC(=O)C1(C)CC(F)(F)C1(F)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C(=O)O)CC(F)(F)C1(F)Cl
Reaction time: 3 h
Yield: 87.9 %

Procedure:
573 g(2.65 mol) of methyl 1-methyl-2-chloro-2,3,3-trifluor-cyclobutane-1-carboxylate, 233 g (5.8 mol) of sodium hydroxide and 1000 ml of water are stirred at 80° C.for three hours. The mixture is acidifed with concentrated hydrochloric acid and extracted with dichloromethane, and the organic phases are dried and distilled. 472 g (88% of theory) of 1-methyl-2-chloro2,3,3-trifluoro-cyclobutane-1-carboxylic acid are obtained, boiling point: 112°-116° C./21.4 mbar (60% transisomer, 40% cis-isomer).