Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=O)(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.Cl.[CH3:27][O:28][C:29]([C:31]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30]>C(Cl)Cl.CC(=O)OCC>[CH3:27][O:28][C:29]([C:31]1([NH:38][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:30]
Reactant: CC(=O)Oc1cc(C(=O)O)ccc1Cl
Reactant: COC(=O)C1(N)CCCCCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(NC(=O)c2ccc(Cl)c(OC(C)=O)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 125.4 %

Procedure:
The compound of step 1 (200 mg, 0.932 mmol) was dissolved in DCM (16 ml), DMF (12 mg) and oxalyl chloride (362 mg, 2.80 mmol) were added and the mixture was stirred at room temperature until completion of the reaction. The volatiles were evaporated in vacuo and the residue dissolved in DCM. The solution was added to a stirred mixture of 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (194 mg, 0.932 mmol) in EA/saturated sodium hydrogencarbonate solution with cooling in an ice bath. Stirring continued at room temperature for 2 h. The phases were separated, aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound (430 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)CC(O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: O=C(O)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Prepared in a similar manner in 95% yield from ethyl 3,3-bis(p-chlorophenyl)propionate was 3,3-bis(p-chlorophenyl)propionic acid, m.p. 190°-193° C.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]=[C:14]([OH:16])[NH:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[F:22][C:23]([S:26][CH2:27][C:28](Cl)=[O:29])([F:25])[F:24].[OH-].[Na+]>CC(C)=O.C([O-])(O)=O.[Na+]>[F:22][C:23]([S:26][CH2:27][C:28]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]=[C:14]([OH:16])[NH:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:29])([F:25])[F:24]
Reactant: O=C(Cl)CSC(F)(F)F
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3n[nH]c(O)n3)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(CSC(F)(F)F)NC1C(=O)N2C(C(=O)O)=C(CSc3n[nH]c(O)n3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cold solution (-20°) of 7-amino-3-(5-hydroxy-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid (3.39 g., 0.01 mole) in a mixture of acetone (62.5 ml.) and 3% NaHCO3 (62.5 ml.) is added dropwise over a 30 minute period a solution of trifluoromethylmercaptoacetyl chloride (2.24 g., 0.012 mol.) in acetone (20 ml.) The solution is maintained at pH 8 by adding 10% sodium hydroxide as needed. The reaction is stirred for 20 minutes at -15° to -20° and then allowed to warm to room temperature. The solution is washed with ether, covered with ethyl acetate and acidified to pH 2. The aqueous phase is separated and extracted with ethyl acetate. The combined ethyl acetate phases are combined, washed with water, dried, and evaporated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:23][CH:22]([CH2:24][S:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:20]3=[O:33])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH2:34].[OH-].[Li+]>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:22]([OH:34])[CH2:24][S:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]([OH:21])=[O:33])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CSCc4ccccc4)OC3=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSCc3ccccc3)C(=O)O)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[(benzylthio)methyl]-tetrahydrofuran 17a (40 mg, 0.083 mmol) in water (3 mL) and THF (3 mL) is added slowly lithium hydroxide monohydrate (35 mg, 0.82 mmol). The reaction mixture is stirred overnight, then concentrated to dryness. The resulting mixture is diluted with water, and then the mixture is extracted twice with Et2O. The Et2O layer is discarded and the aqueous layer is neutralized carefully with 1N HCl to pH 6, then extracted three times with EtOAc. The combined EtOAc layer is washed with brine, dried over MgSO4 and concentrated to a solid which is recrystallized from EtOAc/hexane (1:4) to give the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[NH2:11][C:12]1[NH:16][N:15]=[C:14]([S:17](Cl)(=[O:19])=[O:18])[N:13]=1>C(#N)C>[NH2:11][C:12]1[NH:16][N:15]=[C:14]([S:17]([NH:4][C:3]2[C:5]([Cl:10])=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=2[Cl:1])(=[O:19])=[O:18])[N:13]=1
Reactant: Cc1ccc(Cl)c(N)c1Cl
Reactant: Nc1nc(S(=O)(=O)Cl)n[nH]1
Solvent: CC#N
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Temperature: 65 °C
Reaction time: 120 h
Yield: 67 %

Procedure:
In a manner similar to that described in Example 3, 8.8 g (0.05 mole) of 2,6-dichloro-3-methylaniline, 9.6 g (0.05 mole) of 5-amino-3-chlorosulfonyl -1,2,4-triazole and 25 ml of dry acetonitrile were stirred at about 65° C. for a total of 5 days. The reaction product was recovered as in Example 3 to obtain 10.8 g of the title compound as white solid, m.p. 240°-241° C. (dec.). This assayed by HPLC to be about 98 percent pure. The methylene chloride washes were concentrated to obtain 2.7 g of solid which was over 80 percent purity unreacted 2,6-dichloro-3-methylaniline. The yield of the desired sulfonamide was therefore 88 percent based on unrecovered aniline.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][N:4]([CH3:25])[C:5]1[N:10]=[C:9]([NH:11][CH3:12])[N:8]=[C:7]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])[CH:6]=1.C(=O)(O)[O-].[Na+].[Br:33]Br>C(Cl)Cl>[Br:33][C:6]1[C:7]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])=[N:8][C:9]([NH:11][CH3:12])=[N:10][C:5]=1[N:4]([CH2:3][C:2]([CH3:27])([CH3:26])[CH3:1])[CH3:25]
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(N(C)CC(C)(C)C)nc(NC)n2)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(Nc2nc(NC)nc(N(C)CC(C)(C)C)c2Br)c1

Procedure:
3-{6-[(2,2-Dimethyl-propyl)-methyl-amino]-2-methylamino-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (33 mg), aq. sat. sodium bicarbonate (0.05 mL) and bromine (14 mg) were stirred in methylene chloride (1 mL) at room temperature for 4 hours. The product (14 mg) was purified with preparative thin layer chromatography. MS (m/z): 449 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH2:3][CH2:4][N:5](C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:7][C:8]=1[C:9]#[N:10].[H][H]>C(O)C.Cl.[Pd]>[ClH:1].[Cl:1][C:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]=1[C:9]#[N:10]
Reactant: [H][H]
Reactant: N#CC1=C(Cl)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#CC1=C(Cl)CCNCC1

Procedure:
1.45 gm (0.005 mol) of benzyl 4-chloro-5-cyano-2,3,6,7-tetrahydro-1H-1-azepine-carboxylate were dissolved in 20 ml of ethyl alcohol by addition of 0.9 ml of semiconcentrated hydrochloric acid, and after the addition of 0.2 gm of palladium-on-charcoal, the mixture was hydrogenated in an autoclave at room temperature and under a hydrogen pressure of 5 bars. After half an hour, the uptake of hydrogen had ended. The catalyst was filtered off, and the filtrate was evaporated in vacuo. The residue was recrystallized from isopropyl alcohol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1ccc(O)cc1
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of 17 gm (0.1 mole) of 3-(4-hydroxyphenyl)propionic acid in 500 ml methanol and 2 ml concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3 A molecular sieves. The solution was heated to reflux for 72 hours and the sieves were exchanged at 24 hours intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 ml toluene and extracted with 3×100 ml water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 15 gm (80%) of a clear oil. The NMR spectrum was consistent with the assigned structure and this material was utilized directly in the next reaction step.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:25][CH3:26])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1C=[C:33]([N:35]2CCN(C)CC2)[CH:32]=[CH:31][C:30]=1N.BrC1N2C(C=NC(S(C)=O)=N2)=CC=1.CN1CCCC1=O>>[CH3:26][O:25][C:13]1[CH:14]=[C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH:16]=[CH:17][C:12]=1[NH:11][C:8]1[N:7]=[CH:6][C:5]2=[CH:4][CH:3]=[C:2]([C:32]3[CH:33]=[N:35][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[N:10]2[N:9]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Agent: CS(=O)c1ncc2ccc(Br)n2n1
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4OC)nn23)cn1
Temperature: 145 °C

Procedure:
(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine: Into a 30 mL vial, [A] 2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamine (1.08 g, 0.00490 mol), [B] 7-Bromo-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (0.580 g, 0.00223 mol) and N-Methylpyrrolidinone (3.50 mL, 0.0363 mol) were added. The reaction mixture was heated at 145° C. for 2.5 hours. The solvent was removed under vacuum to give a solid. The solid was partitioned with water and DCM. The organic was separated, washed with Brine and dried over sodium sulfate. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and MeOH as eluant (3 to 10% methanol). The collected fractions afforded (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a yellow solid (0.58 g, 62%). NMR 1H (DSMO-d6)-8.83 (s, 1H), 8.03 (d, 1H, J=8.76 Hz), 7.75 (s, 1H), 6.92 (d, 1H, J=4.58 Hz), 6.86 (d, 1H, J=4.68 Hz), 6.67 (d, 1H, J=2.24 Hz), 6.49 (dd, 1H, JJ=2.32, 6.44 Hz), 3.85 (s, 3H), 3.12 (t, 4H, J=4.64 Hz), 2.46 (t, 4H, J=4.84 Hz), 2.22 (s, 3H)
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([NH2:5])=O.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([N:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]#[N:5])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)C1CCCCN1
Product: CC(=O)N1CCCCC1C#N
Yield: 67 %

Procedure:
An amount of 19.2 g. (0.15 moles) of pipecolamide is added portionwise to 102 g. (1.0 moles) of acetic anhydride over a 15 minute period with stirring. The temperature rises to ca. 60°C. The mixture is then heated to reflux, during which the solid dissolves and the solution turns a dark brown. After refluxing for 4 hours, the reaction mixture is subjected to vacuum distillation (first at 60 mm Hg to remove acetic acid and excess acetic anhydride, and then at 1-4 mm Hg pressure). Thus is obtained 15.3 grams of 1-acetyl-2-cyanopiperidine, boiling at 104°-14°C. This corresponds to a 67% yield based on pipecolamide.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:42])C.[OH-].[Na+].Cl>C(O)C>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][O:32][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:43])=[O:3])=[C:8]([CH3:42])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[CH:17]=2)=[CH:36][CH:37]=1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCCc3ccc(Cl)cc3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (190 mg; 0.30 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 160 mg (89%). HPLC-MS: m/z: 607.1 (M+H)+; Rt: 2.82 min.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[O:16]C)([CH3:3])[CH3:2].O.C(OCC)C>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: COc1c(-c2ccccc2)cccc1C(C)C
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CC(C)c1cccc(-c2ccccc2)c1O
Reaction time: 12 h
Yield: 94 %

Procedure:
A mixed solution of 8 mL of water and 32 mL of dimethoxyethane was added into a flask into which 2-bromo-6-isopropylanisole (1.98 g, 8.64 mmol), phenylboronic acid (2.10 g, 17.28 mmol), palladium acetate (96 mg, 0.43 mmol), triphenylphosphine (0.225 g, 0.86 mmol), and potassium phosphate (11 g, 51.84 mmol) were already added, and then refluxed at normal temperature for 12 hours. After cooling to normal temperature, an ammonium chloride aqueous solution (15 mL) and 30 mL of diethylether were added thereto to separate an organic layer and extract residues using diethylether. The separated organic layer was dried with magnesium sulfate and volatile materials were removed to produce 2 g of grey 2-isopropyl-6-phenylanisole solid. The anisole thus produced was dissolved in 15 mL of methylene chloride without separate purification, 12 mL of boron tribromide (1 M methylene chloride solution) were dropped thereonto at −78° C., and the reaction was carried out for 12 hours while the temperature was slowly increased to normal temperature. After the reaction, a mixed solution of water (15 mL) and diethylether (30 mL) was added to separate an organic layer and extract an aqueous solution layer using diethylether (15 mL×3), and the separated organic layer was dried. Residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and methylene chloride to produce 1.72 g of white 2-isopropyl-6-phenylphenol solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[N:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]2)[O:4]CC1>CC(O)=O.C1COCC1.O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[C:13]2[CH2:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1
Reactant: COc1ccc2nccc(CCC3CCC4(CC3)OCCO4)c2c1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2nccc(CCC3CCC(=O)CC3)c2c1

Procedure:
A solution of 4-[2-(1,4-dioxa-spiro[4.5]dec-8-yl)-ethyl]-6-methoxy-quinoline (0.77 g, 2.35 mmol) in AcOH/THF/H2O (3/2/2, 10 ml) was stirred at 60° C. for 10 hours. The reaction mixture was concentrated to dryness by rotary evaporation. The residue was diluted with EtOAc (100 ml), washed with NaHCO3 (100 ml), dried over MgSO4, filtered and concentrated to dryness by rotary evaporation.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[C:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]1[CH2:32][CH2:33][CH:28]([C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=2)[CH2:29][CH2:30]1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1cccc(OCCCCCCl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(=O)c1cccc(OCCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{3-[(5-chloropentyl)oxy]phenyl}ethanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 451.3 (M+H)+.
Reaction SMILES: [CH2:1]1[N:6]2[CH2:7][N:8]3[CH2:10][N:4]([CH2:5]2)[CH2:3][N:2]1[CH2:9]3.O[Mo:12](O)(=O)=O.[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O>O>[Mo:12].[CH2:1]1[N:6]2[CH2:7][N:8]3[CH2:10][N:4]([CH2:5]2)[CH2:3][N:2]1[CH2:9]3
Reactant: O=[Mo](=O)(O)O
Agent: O=[Mo](=O)([O-])[O-]
Agent: C1N2CN3CN1CN(C2)C3
Agent: [NH4+]
Solvent: O
Product: [Mo]

Procedure:
Hexamethylenetetramine molybdate having a 2/1 molybdenum/hexamethylenetetramine molar ratio was prepared as follows. 10 grams of hexamethylenetetramine was dissolved in 100 ml water heated near reflux temperature. 24.01 grams of commercial, so-called "molybdic acid" (actually at least one ammonium molybdate) was dissolved in 169 ml water heated to reflux temperature. The first solution was added to the second solution.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[CH:5]=[CH:4][N:3]=1.[OH-:23].[K+]>C(O)(C)(C)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:23])[CH:7]=3)[CH:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccnc(Cl)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cc[nH]c(=O)c1
Yield: 91.8 %

Procedure:
2-chloro-4-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-pyridine (120 mg, 0.366 mmol) was dissolved in 6 ml tert-butanol. A 50% solution of KOH (2 ml, 26.7 mmol) was added and the mixture was refluxed for 72 h. The reaction mixture was concentrated in vaccuo, the pH was adjusted to 7 by addition of 37% HCl solution, and the aqueous phase was extracted twice with 40 ml of ethyl acetate. The organic phase was washed once with 10 of brine, dried with magnesium sulfate, filtered and evaporated. The title compound (104 mg, 0.336 mmol, 92%) was obtained as a crystalline light yellow solid, MS: m/e=310.1, 312.2 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([O:22][CH:23]([CH3:25])[CH3:24])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([O:22][CH:23]([CH3:24])[CH3:25])[CH:10]=1
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)cc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (E)-ethyl 3-(4-(benzyloxy)-2-isopropoxyphenyl)acrylate (699) (530 mg, 1.56 mmol) in ethanol (12 mL) was added Pd/C (0.5 eq, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight at room temperature, filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(4-hydroxy-2 isopropoxyphenyl)propanoate (700).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH2:30][OH:31])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[O:16]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:27]2[CH2:26][CH2:25][N:24]([C:23]3[CH:22]=[CH:21][C:20]([CH2:30][OH:31])=[CH:19][C:18]=3[CH3:17])[CH2:29][CH2:28]2)=[O:13])=[CH:14][CH:15]=1
Reactant: Cc1cc(CO)ccc1N1CCNCC1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Product: Cc1cc(CO)ccc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2)CC1
Yield: 52.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (378 mg) described in Preparation Example 16 and [3-methyl-4-(piperazin-1-yl)phenyl]methanol (323 mg) described in Preparation Example 98 and by the reaction and treatment in the same manner as in Example 87, the title compound (351 mg) was obtained.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O=[Pt]=O>[C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2nnc3cnccc32)cc1
Agent: O=[Pt]=O
Solvent: CO
Product: c1ccc(-n2nnc3c2CCNC3)cc1
Yield: 56.4 %

Procedure:
A solution of 1-phenyl-1H-[1,2,3]triazolo[4,5-c]pyridine (61 mg, 0.31 mmol) in MeOH (15 ml) was passed through a PtO2 catalyst cartridge on an H-Cube hydrogenation apparatus at a pressure of 70 bar and a flow rate of 1 ml/min. The reaction was concentrated and the crude reaction mixture purified on 12 g SiO2 column with 0-8% NH3/MeOH CH2Cl2 to give 35 mg (56%) of 1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine. MS (ESI): mass calcd. for C11H12N4, 200.2. m/z found, 201.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.99 (dt, J=8.0, 1.1 Hz, 2H), 7.61-7.50 (m, 2H), 7.48-7.41 (m, 2H), 7.33-7.27 (m, 1H), 4.14-4.07 (m, 2H), 3.20 (t, J=5.9 Hz, 2H), 2.88 (t, J=5.9 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[N:22][C:23]([N:26]6[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]6)=[CH:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:5][CH:4]=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[N:22][C:23]([N:26]6[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]6)=[CH:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(N5CCN(C)CC5)nc4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(N5CCN(C)CC5)nc4)cc2-3)cc1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
6-(4-Methoxy-phenyl)-2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.33 g, 5.5 mmol) was dissolved in MeOH and treated with concentrated HCl (0.2 mL, 5.5 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-(4-Methoxy-phenyl)-2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.26 g, 5.2 mmol) as white solid in 95% yield.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=O)[C:2]=1[C:10]([OH:12])=[O:11]>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:10]1(=[O:11])[O:12][C:7](=[O:9])[CH:3]2[CH2:4][CH2:5][CH2:6][CH:1]=[C:2]12
Reactant: O=C(O)C1=CCCCC1C(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2CCCC=C12
Yield: 49.9 %

Procedure:
A stirred solution of 5.0 grams (0.029 mole) of cyclohexene-2,3-dicarboxylic acid in 30 ml of acetic anhydride and 100 ml of acetic acid was heated under reflux for four hours. The reaction mixture was concentrated under reduced pressure to a residual oil. The oil was washed with petroleum ether and evacuated under high vacuum to yield 2.2 grams of 2,3,4,5-tetrahydrophthalic anhydride as a semi-solid.