Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[CH2:17][C:18](=O)[CH3:19]>CC(C)=O>[CH3:19][C:18]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:2]2[N:1]([CH:17]=1)[CH:6]=[CH:5][CH:4]=[CH:3]2
Reactant: CC(=O)CBr
Reactant: CCOC(=O)CCCCc1ccccn1
Solvent: CC(C)=O
Product: CCOC(=O)CCCc1c(C)cn2ccccc12

Procedure:
To a solution of ethyl 5-(2-pyridyl)pentanoate (1.07 g) in acetone (5 ml) was added bromoacetone (0.51 ml) and the mixture was refluxed for 2 hours. After removal of the solvent, the residue was dissolved in aqueous sodium bicarbonate (1 g sodium bicarbonate/20 ml water) and then refluxed for 30 minutes. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, evaporated in vacuo, and chromatographed on silica gel (dichloromethane) to give ethyl 4-(2-methylindolizin-1-yl)butyrate (778 mg).
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[CH2:9]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](OCC3C=CC=CC=3)=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[ClH:1].[CH2:9]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([NH:4][C:3]([NH2:5])=[NH:2])=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N=C(N)N
Reactant: O=C(OCc1ccccc1)c1ccc2c(ccn2Cc2ccccc2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)NC(=O)c1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 55 °C
Reaction time: 30 h
Yield: 10.4 %

Procedure:
After 2.24 g (23.4 mmol) of guanidine hydrochloride was added to 50 ml of a methanol solution of 1.26 g (23.4 mmol) of sodium methoxide, 0.80 g (2.34 mmol) of benzyl 1-benzyl-5-indolecarboxylate was added to the resulting mixture. The mixture was then stirred for 30 hours while heating at 50 to 60° C. Methanol was distilled off under reduced pressure and the residue was purified by silica gel column chromatography followed by treatment with 2N hydrochloric acid to give 0.08 g (10.4%) of 1-benzyl-5-indoloylguanidine hydrochloride.
Reaction SMILES: [N:1]([CH:4]([C:7]1[N:8]=[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:10]2[C:11](=[O:14])[C:12]=1I)[CH2:5][CH3:6])=[N+:2]=[N-:3].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[N:1]([CH:4]([C:7]1[N:8]=[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:10]2[C:11](=[O:14])[C:12]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][CH3:6])=[N+:2]=[N-:3]
Reactant: OB(O)c1ccccc1
Reactant: CCC(N=[N+]=[N-])c1nc2cccc(C)n2c(=O)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(N=[N+]=[N-])c1nc2cccc(C)n2c(=O)c1-c1ccccc1
Temperature: 100 °C
Yield: 54 %

Procedure:
To a mixture of 2-(1-azidopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.11 g, 0.29 mmol) and phenylboronic acid (42.9 mg, 0.352 mmol) in 1,4-dioxane (2 mL) was added a 1 M solution of sodium carbonate (37.3 mg, 0.352 mmol) in water (0.35 mL) and tetrakis(triphenylphosphine)palladium (0) (16.9 mg, 0.0147 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to provide the desired product (50 mg, 53.4%). LCMS calculated for C18H18N5O (M+H)+: m/z=320.2. Found: 320.3.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:14]([NH2:16])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:14]#[N:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(F)cc2CC1C(N)=O
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccc(F)cc2CC1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a suspension of intermediate (18) (0.0076 mole) in DCM (30 ml), cooled in an ice bath under argon, was added triethylamine (0.0228 mole) followed by trichloroacetyl chloride (0.0115 mole). The mixture was allowed to warm to room temperature and stir for 2 hours. The mixture was washed with water, 2N HCl, and saturated NaHCO3. The organic layer was dried and concentrated. The concentrate was triturated in ether and purified on silica gel column, eluting with 50% ethyl acetate in hexane. The desired fractions were combined and concentrated. The residue was triturated in ether and the solid collected by filtration and allowed to dry, yielding 0.30 g of 1-acetyl-5-fluoro-2,3-dihydro-1H-indole-2-carbonitrile (intermediate 19, mp. 93-95° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([Br:30])[N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Yield: 62.6 %

Procedure:
A mixture of 1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (81 mg, 0.21 mmol) and N-bromosuccinimide (40 mg, 0.23 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-15% EtOAc/hexanes+1% AcOH) to give 62 mg of the title compound as a light yellow solid. MS: (−) m/z 469.20, 471.15 (M-1, 79/81Br).
Reaction SMILES: [C:1]1([CH:7]([C:13](OCC)=[O:14])[C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]1([CH:7]([CH2:8][OH:9])[CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC(CO)c1ccccc1

Procedure:
Diethyl phenylmalonate is reduced with lithium aluminium hydride to give 2-phenyl-propane-1,3-diol and esterified with an equimolar amount of benzenesulphochloride in anhydrous pyridine to give 2-phenylpropane-1,3-diol monobenzenesulphonate (wax-like substance). Reaction thereof with the potassium salt of hexadecanethiol in ethanol gives the desired 3-hexadecylthio-2-phenylpropan-1-ol (wax-like substance).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=O)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].Cl.Cl.Cl.[N:21]1([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH:32]([NH:35][C:15]([C:12]3[S:11][C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]=4[CH:13]=3)=[O:17])[CH2:33][CH2:34]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCN(CCN2CCCCC2)CC1
Reactant: CC(C)COc1cccc2sc(C(=O)O)cc12
Agent: Cl
Product: CC(C)COc1cccc2sc(C(=O)NC3CCN(CCN4CCCCC4)CC3)cc12

Procedure:
This compound is synthesized from compound 202 and amine 1 analogously to the method described in Example 178.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH2:23][CH2:22][C:21](=O)[CH2:20]1>>[F:15][C@H:14]1[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]([NH:1][CH:21]2[CH2:22][CH2:23][O:19][CH2:20]2)[CH:3]=[CH:4][C:5]=1[F:18])[CH3:17]
Reactant: O=C1CCOC1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Product: C[C@]1(c2cc(NC3CCOC3)ccc2F)N=C(N)COC[C@@H]1F
Yield: 44.7 %

Procedure:
In an analogous manner as described for example 1 the reductive amination of (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine (intermediate A10B) (20 mg, 78.4 μmol) and dihydrofuran-3(2H)-one (3-oxotetrahydrofuran) (CAS [22929-52-8]) (7.42 mg, 6.67 μl, 86.2 μmol) yielded the title compound (11.4 mg, 44.7%) as a colorless solid. MS (ISP): m/z=326.3 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[C:7]([O:9]C)=[O:8]>CO>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CON=C(C(=O)OC)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 96.8 %

Procedure:
A 2N aqueous solution of sodium hydroxide (14 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetate (syn isomer) (3.5 g.) in methanol (70 ml.) and the mixture was stirred for 60 hours at ambient temperature. The reaction mixture was concentrated to dryness at 40° C. under reduced pressure and the residue was dissolved in water. The solution was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract was back-extracted with a saturated sodium bicarbonate aqueous solution. The aqueous extract was adjusted to pH 1 with conc. hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract was washed with ice-water and dried over magnesium sulfate. The solvent was concentrated to dryness at 40° C. under reduced pressure to give yellow crystals of 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetic acid (syn isomer) (3.2 g.), mp 142° to 143° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=[C:31]([NH2:44])[N:30]=1>>[CH3:28][C:29]1[C:34]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:33][N:32]=[C:31]([NH2:44])[N:30]=1
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (300 mg), prepared according to General Procedure B-3, was coupled to 4-methyl-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine via General Procedure A to yield 36.1 mg of 348. MS (Q1) 505.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=O)[C:7](=[CH:19][N:20]([CH3:22])C)[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.C(O)(=O)C.C(N)=[NH:31]>C(N)=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:31]=[CH:22][N:20]=[CH:19][C:7]=3[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: N=CN
Reactant: CN(C)C=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Solvent: NC=O
Solvent: CC(=O)O
Product: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc2C1

Procedure:
A mixture of 0.4 g (1.1 mmol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one 2-oxide, 1.0 g (9.6 mmol) of formamidine acetate and 20 ml of formamide was heated on a steam bath for 6 hr. The mixture was poured over ice and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue crystallized with the addition of a mixture of ether and methylene chloride to give off-white crystals, mp 186°-188° C.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH:7]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH3:31]I.O>CN(C)C=O>[CH3:1][C:2]([CH3:28])([CH:7]([N:17]([CH3:31])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: CI
Reactant: COC(=O)C(C)(C)C(Cc1ccc(OC)cc1)NS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)C(Cc1ccc(OC)cc1)N(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Yield: 96 %

Procedure:
A solution of 405 g of methyl 2,2-dimethyl-4-(p-methoxyphenyl)-3-(p-toluenesulphonamido)butyrate in 1800 ml of dry dimethylformamide is added to a mechanically stirred suspension of 52.8 g of sodium hydride in 320 ml of the same solvent. After the reaction mixture has been heated at 80° C. for 1 hour it is cooled when 93 ml of methyl iodide is added. After an additional period of heating (under reflux) the mixture, after being cooled, is poured into plenty of water. A white crystallisate separates. After filtration and drying it melts at 132°-134° C. Yield 96%.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:11][CH2:10]2)[N:4]=1.CO.O.[OH-].[Li+]>O1CCCC1>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:10][CH2:11][CH:12]([CH2:15][NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:14]2)[N:4]=1
Reactant: COC(=O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cc1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 81 %

Procedure:
Methyl 4-{[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}benzoate was dissolved in 24 ml of tetrahydrofuran, 23 ml of methanol, and 23 ml of water. To this solution was added lithium hydroxide (817 mg) and the mixture was stirred at 50° C. for 1.25 h. The solvents were removed in vacuo and the residue was taken up in 1 N HCl (70 ml) and 70 ml of ethyl acetate. The mixture was sonicated until the solid residue mostly dissolved in the ethyl acetate. The two phases were separated, and any remaining product in the aqueous layer was extracted out with ethyl acetate (70 ml). The organic layers were combined, washed with brine (20 ml), and concentrated in vacuo to yield the title compound (1.09 g, 81%). Mass spectrum (ESI) 409.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:28])[C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([OH:27])[CH:20]=3)[CH2:13][CH2:12]2)[CH:7]=[C:6]([O:29][CH2:30][CH3:31])[C:5]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH3:2].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:19]3[CH:20]=[C:21]([O:27][S:40]([CH3:39])(=[O:42])=[O:41])[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=3)=[O:28])[CH2:13][CH2:12]2)[CH:7]=[C:6]([O:29][CH2:30][CH3:31])[C:5]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OS(C)(=O)=O)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 72a), N-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-3-hydroxy-5-methoxy-benzamide (example 259) was reacted with methanesulfonyl chloride, N-ethyl-diisopropylamine in CH2Cl2 at rt to yield the title compound as colorless solid. MS: 601.3 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:11](O)[CH2:12][OH:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[C:5]1([C:3]2([CH2:2][OH:1])[O:13][CH2:12][CH2:11][O:4]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCCO
Reactant: O=C(CO)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: OCC1(c2ccccc2)OCCO1
Yield: 97.7 %

Procedure:
2-Hydroxy-1-phenylethanone (49.39 g, 297 mmol), ethylene glycol (84 mL, 1500 mmol), p-toluenesulfonic acid monohydrate (1.0 g) and benzene (500 mL) were added to a one-liter eggplant type flask equipped with a Dean-Stark dehydrating device and heated to reflux for 24 hours. The solvent was evaporated in vacuo, water and ethyl acetate were added to the resulting residue and the organic layer was separated. An aqueous layer was further extracted with ethyl acetate twice and the organic layers were combined and washed with a saturated saline solution. It was dried over anhydrous sodium sulfate, the solvent was evaporated therefrom in vacuo and the resulting crude product was purified by a silica gel column chromatography (toluene:ethyl acetate=4:1) to give (2-phenyl-[1,3]dioxolan-2-yl)methanol (52.30 g, 98%) as an oily product. 1H-NMR (DMSO-d6) δ: 3.51 (d, J=6.4 Hz, 2H), 3.74-3.78 (m, 2H), 4.01-4.05 (m, 2H), 4.09 (t, J=6.4 Hz, 1H), 7.28-7.36 (m, 3H), 7.40-7.43 (m, 2H).
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:9])C=C[CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[N:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1>C(O)CCC>[CH2:3]([O:9][C:11]1[N:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1)[CH2:4][CH2:5][CH3:6]
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCOc1ccc(N2CCN(c3cccc(C)c3)CC2)nn1
Yield: 64 %

Procedure:
To a stirred mixture of 80 parts of 1-butanol, 0.4 parts of sodium hydroxide and 0.94 parts of phenol were added 2.2 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine at 60° C. The whole was stirred and refluxed over weekend. The reaction mixture was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (64%) of 3-butoxy-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine: mp. 105.2° C. (compound 257).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:35][CH2:36][C:37]([CH3:40])([OH:39])[CH3:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([C:32]([NH:35][CH2:36][C:37]([OH:39])([CH3:40])[CH3:38])=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: CC(C)(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(O)CNC(=O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carboxylic acid (0.205 g) in N,N-dimethylformamide (5 mL) were added 1-amino-2-methyl-propan-2-ol (76 mg), triethylamine (0.18 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (123 mg) and 1-hydroxybenzotriazole (98 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column 15 chromatography (ethyl acetate:hexane=40:60-100:0, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (0.126 g, yield 53%) as colorless crystals. MS: 552 (MH+). melting point 126-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH2:17]O.P(Br)(Br)[Br:20].C([O-])(O)=O.[Na+]>C1COCC1>[Br:20][CH2:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:4]=1[Cl:16]
Reactant: OCc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 222.1 %

Procedure:
Treat a 0° C. solution of (2,6-dichloro-4-benzyloxy-phenyl)-methanol (247 g, 0.872 mol) in THF (2.5 L) with phosphorous tribromide (94.45 g, 0.35 mol) and stir for 30 minutes at 0° C. under N2. Pour the reaction into saturated NaHCO3 and extract twice with ethyl acetate. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford 269 g (89%) of the titled product. ES MS (m/z): 346 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23](O)=[O:24]>>[CH3:32][O:31][C:27]1[CH:26]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[C:28]=1[O:29][CH3:30])[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:24]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: COc1cc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc(OC)c1OC
Yield: 74.1 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 27.8 mg (0.131 mMol) 3,4,5-trimethoxybenzoic acid, 13.8 mg (75%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH:23]([OH:25])[CH3:24])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:4][CH:3]=1.CO.C#C>C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:27][CH:28]=1
Reactant: CC(O)C#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Agent: C#C
Solvent: CO
Solvent: ClCCl
Product: CC(O)CCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-butynyl)-3-quinolinecarboxamide from Example No. 96 (173.7 mg) and Pd/C (10%, 34.7 mg) was dissolved in 3:1 CH2Cl2 :MeOH. The reaction mixture was placed under the Parr hydrogenator and monitored with the OAMS for complete reduction of the acetylene. The reaction was completed in 1 hr and filtered over celite to remove the palladium. The filtrate was condensed to obtain a yellow solid. The crude product was recrystallized with EtOAc/hexanes to yield 123.8 mg (71%) of the desired product as an off-white solid.