Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2([OH:33])[CH2:18][CH2:17][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)(=O)=O)=CC=1.[I-:35].[Na+]>CC(=O)CC>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[N:16]1[CH2:17][CH2:18][C:13]([OH:33])([CH2:12][CH2:11][I:35])[CH2:14][CH2:15]1
Reactant: [I-]
Reactant: COc1cc2ncnc(N3CCC(O)(CCOS(=O)(=O)c4ccc(C)cc4)CC3)c2cc1OC
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2ncnc(N3CCC(O)(CCI)CC3)c2cc1OC

Procedure:
A mixture of 1-[4-toluenesulphonyloxy]-2-[1-(6,7-dimethoxyquinazolin-4-yl)-4-hydroxy-piperid-4-yl]ethane (0.6 g) and sodium iodide (1.84 g) in butan-2-one (10 cm3) was heated under reflux for 2.5 hours. Volatile material was removed in vacuo and the residue partitioned between chloroform (20 cm3) and water (20 cm3). The dried (MgSO4) organic phase was evaporated and the residue was crystallized from ethyl acetate to afford 6,7-dimethoxy-4-[4-hydroxy-4-(2-iodoethyl)piperid-1-yl]quinazoline, m.p. 179°-181°, (0.3 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.[CH2:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:17]>C(#N)C>[Br-:1].[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]#[C:4][CH2:3][CH2:2][N+:20]2[CH:21]=[CH:22][CH:23]=[C:18]([CH2:16][CH3:17])[CH:19]=2)=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCc1cccnc1
Reactant: CCCCc1ccc(C#CCCBr)cc1
Solvent: CC#N
Product: CCCCc1ccc(C#CCC[n+]2cccc(CC)c2)cc1
Product: [Br-]
Yield: 67 %

Procedure:
1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solution of 3-ethylpyridine (3 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no ethylpyridine was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (67%). 1HNMR (300 MHz, CDCl3, ppm), 9.43 (d, J=6.0, 1H), 9.41 (s, 1H), 8.25 (d, J=8.1, 1H), 7.96 (dd, J=6.0, J=8.1, 1H), 7.15 (d, J=8.1, 2H), 7.06, d, J=8.1, 2H), 5.26 (t, J=6.0, 2H), 3.26 (t, J=6.0, 2H), 2.90 (q, J=7.5, 2H), 2.56 (t, J=8.1, 2H), 1.49-1.59 (m, 2H), 1.27-1.37 (m, 5H), 0.90 (t, J=7.2, 3H); 13CNMR, 144.65, 144.46, 144.14, 143.65, 142.45, 131.14, 128.30, 127.12, 118.87, 85.88, 82.45, 59.99, 35.45, 33.27, 26.01, 22.85, 22.21, 14.26, 13.88.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[C:8]([CH2:15]O)=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1.CCN(CC)CC>C(Cl)Cl>[Br:6][C:7]1[C:8]([CH2:15][S:2]([CH3:1])(=[O:4])=[O:3])=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ncc(Br)c(CO)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ncc(Br)c(CS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (5.85 g, 51.0 mmol) was added to a stirred, cooled 0° C. mixture of [5-bromo-2-(methylthio)pyrimidin-4-yl]methanol (INTERMEDIATE 1, 10 g, 42.5 mmol) in CH2Cl2 (200 mL), followed by addition of Et3N (6.46 g, 63.8 mmol). The mixture was stirred at 0° C. for 30 minutes. TLC showed no starting material left. The mixture was quenched with water (30 mL) and the mixture was washed with more water (50 mL). The organic portion was washed with brine (saturated, 50 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography, eluting with EtOAc/hexane (3/7) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 8.61 (s, 1H), 5.38 (s, 2H), 3.21 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>CN(C=O)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([N:9]2[CH2:8][CH:7]([CH2:6][N:31]3[CH2:30][CH2:29][C:28]([C:25]4[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=4)([OH:34])[CH2:33][CH2:32]3)[O:11][C:10]2=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc(N2CC(COS(C)(=O)=O)OC2=O)cc1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CN(C)C=O
Product: COc1ccc(N2CC(CN3CCC(O)(c4ccc(Cl)cc4)CC3)OC2=O)cc1

Procedure:
4.82 g of 5-methanesulfonyloxymethyl-3-p-methoxyphenyl-oxazolidin-2-one [m.p. 126°-128°; obtainable by reaction of p-methoxyaniline with hydroxymethyl-oxirane to give 3-p-methoxyanilino-1,2-propanediol, reaction with diethyl carbonate to give 3-p-methoxyphenyl-5-hydroxymethyl-oxazolidin-2-one (m.p. 133°-134°) and reaction with CH3SO2Cl] is heated together with 5.08 g of 4-p-chlorophenyl-4-hydroxypiperidine in 25 ml of DMF at 95°-100° for 1 hour; the mixture is cooled and worked up in a conventional manner to give 3-p-methoxyphenyl-5-(4-p-chlorophenyl-4-hydroxy-piperidinomethyl)-oxazolidin-2-one, m.p. 143°-144°.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]>O1CCOCC1.[OH-].[Na+]>[CH2:1]([S:3]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: NCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)NCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A solution of ethanesulfonyl chloride (1.5 ml, 15.7 mmol) in dioxane (5 ml) was added to a solution of 8-aminooctanoic acid (1 g, 6.28 mmol) in 1N NaOH (22 ml) and dioxane (5 ml), while stirring at 0–5° C. The mixture was allowed to warm to room temperature and stirred for 3.5 minutes. During this period, at 1 hour intervals, the pH was adjusted to 7–8 by addition of 25% NaOH solution. The reaction mixture was washed with diethyl ether (30 ml). The pH was adjusted to 1–2 by addition of 1N HCl and the mixture was extracted with ethyl acetate (70 ml). The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with a mixture of diethyl ether. The solid was collected by filtration and dried under vacuum affording 600 mg of the title compound (38% yield). 1H NMR (DMSO-d6): 11.9 (1H, s); 6.96 (1H, t, J=6 Hz); 2.96 (2H, q, J=7.1); 2.88 (2H, q, J=6.6); 2.2 (2H, t, J=7.3); 1.45 (4H, m); 1.26 (6H, m); 1.18 (3H, t, J=7.3).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH:13]=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10]1)=O)(C)(C)C.C(N(CC)CC)C.[Cl:25]C(OC)=O.[CH2:30]([NH2:33])[CH2:31][CH3:32]>ClCCl>[ClH:25].[CH2:30]([NH:33][C:15]([C:11]1[CH:12]=[CH:13][CH2:14][CH:9]([NH2:8])[CH:10]=1)=[O:17])[CH2:31][CH3:32]
Reactant: CC(C)(C)OC(=O)NC1C=C(C(=O)O)C=CC1
Reactant: COC(=O)Cl
Reactant: CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)C1=CC(N)CC=C1
Product: Cl
Reaction time: 18 h

Procedure:
A solution of 240 mg (1 m mole) of 3-tert-butoxycarbonylamino-1,5-cyclohexadiene carboxylic acid in 5 ml of dichloromethane is treated with 202 mg (2 m mole) of triethylamine and 94 mg (1 m mole) of methyl chloroformate. After 30 minutes at 25° C. the solution is treated with 60 mg (1 m mole) of n-propylamine for 1 hour at 25° C. after which the solution is diluted with dichloromethane, washed with water, dryed and evaporated. The residue is stirred for 18 hours in 7 ml of methanol and 3.5 ml of 5% aqueous HCl. Evaporation affords N-propyl-3-amino-1,5-cyclohexadienecarboxamide hydrochloride.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].O[C:10]1[S:14][C:13](O)=[C:12](O)[C:11]=1O>CC(C)=O>[Br-:1].[O:8]=[C:3]([C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:2][S+:14]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Oc1sc(O)c(O)c1O
Reactant: CC(C)(C)C(=O)CBr
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)C[S+]1CCCC1
Product: [Br-]
Yield: 142.7 %

Procedure:
In a 300 ml three-necked flask, 2 g of tetrahydroxythiophene was dissolved in 20 ml of acetone. To the solution, 4.87 g of 1-bromo-3,3-dimethy 2-butanone was added dropwise while stirring. After leaving for 24 hours, the deposited white crystal was collected by filtration. The white crystal was ground to a powder, which was washed with ether. The powder was dried by a vacuum drier at 30° C. for six hours to obtain 5.15 g of 2-oxo-3,3-dimethylbutyl-thiacyclopentanium bromide (yield: 75.0%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:17][CH2:16]3)[C:5]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:4][N:3]=1.C(O)C.O.O[Li].O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([OH:25])=[O:24])[CH2:17][CH2:16]3)[C:5]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:4][N:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3-c3ccc(OC)cc3)ccc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cnc(Cl)nc2N(C)CCCOc2ccc3c(c2)CC[C@H]3CC(=O)O)cc1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[[2-chloro-5-(4-methoxyphenyl)-4-pyrimidinyl](methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 443, 70 mg, 0.137 mmol) in a mixture of THF (2 mL), ethanol (1 mL), and water (2 mL) was added LiOH.H2O (13 mg, 0.55 mmol). The mixture was maintained at rt in an orbital shaker for 16 h after which the reaction mixture was washed with Et2O. To the remaining aqueous solution was added HCl (1N aqueous solution) dropwise until pH 5 was reached. The aqueous solution was then extracted with EtOAc, the combined organic layers dried (Na2SO4), filtered, and concentrated under reduced pressure to give 20 mg (30%) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.75-1.79 (m, 1H), 2.18-2.21 (m, 2H), 2.24-2.49 (m, 2H), 2.77-2.90 (m, 3H), 3.31 (s, 3H), 3.52-3.74 (m, 1H), 3.92 (s, 3H), 3.99 (t, 2H), 4.05 (t, 2H), 6.67 (d, 1H), 6.75 (s, 1H), 6.94 (d, 2H), 7.08 (s, 1H), 8.15 (s, 1H), 8.27 (d, 2H); LC-MS: RT=2.91 min, (M+H)+ 482.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[OH:17])[CH3:4].[H][H].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[S:24]>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[O:17][C:23](=[S:24])[N:22]([CH3:26])[CH3:21])[CH3:4]
Reactant: [H][H]
Reactant: CN(C)C(=S)Cl
Reactant: CCOC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Br)cc([N+](=O)[O-])c1OC(=S)N(C)C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
To a suspension of NaH (760 mg, 40%, 19 mmol) in DMF (50 mL) is added the 5-Bromo-2-hydroxy-3-nitro-benzoic acid ethyl ester (4.22 g, 18.2 mmol) portionwise over 5 minutes. After all the hydrogen gas is evolved the reaction is stirred for an additional 10 minutes and then an additional 100 mL, of dry DMF is added. The reaction is stirred at room temperature for 1 minute and dimethylthiocarbamoyl chloride (2.4 g, 18.9 mmol) is added over 5 minutes (Caution stench). The resulting reaction is stirred at room temperature for three days and then checked for completion by LC/MS. Reaction is quenched with water and extracted with ethyl acetate and dichloromethane to give 5.2 g (90%) of the crude product 80% pure, used without further purification. LCMS (ESMS): m/z 378.3 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][NH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28](O)=[O:29]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:28]([C:27]4[CH:31]=[CH:32][N:33]=[C:25]([NH:24][CH3:23])[CH:26]=4)=[O:29])[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Reactant: CNc1cc(C(=O)O)ccn1
Agent: Cl
Product: CNc1cc(C(=O)N2CCC[C@H](COc3cccc4c3C(N)=NS(=O)(=O)N4)C2)ccn1
Yield: 44 %

Procedure:
Prepared as in Example 2 from (S)-4-amino-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 2a) and 2-(methylamino)isonicotinic acid. (Yield: 44%). 1H NMR (400 MHz, DMSO-d6, 60° C.) δ 1.45 (br m, 2H), 1.68 (br m, 1H), 1.91 (br m, 1H), 2.15 (br m, 1H), 2.77 (d, J=7.6 Hz, 3H), 3.02 (br m, 1H), 1.97 (br m, 1H), 2.13 (br m, 2H), 2.80 (br m, 2H), 3.19 (br m, 1H), 3.30-4.09 (br m, 4H), 6.34 (br m, 1H), 6.38 (br m, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.74 (m, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.73 (br s, 2H), 8.01 (m, 1H), 10.70 (br s, 1H). MS 445 (MH+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[NH2:9][C:10]1[C:15]([O:16][CH3:17])=[N:14][C:13]([Cl:18])=[CH:12][N:11]=1.N1C=CC=CC=1.Cl>ClCCl>[Cl:18][C:13]1[N:14]=[C:15]([O:16][CH3:17])[C:10]([NH:9][C:2](=[O:3])[O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[N:11][CH:12]=1
Reactant: CC(C)COC(=O)Cl
Reactant: COc1nc(Cl)cnc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nc(Cl)cnc1NC(=O)OCC(C)C
Reaction time: 20 h
Yield: 78.9 %

Procedure:
Isobutyl chloroformate (4.1 g) was added to a solution of 2-amino-5-chloro-3-methoxypyrazine (4.8 g) and pyridine (2.37 g) in dichloromethane (50 ml). The solution was left to stand for 20 hours and then two further portions of isobutyl chloroformate (1.02 g) and pyridine (0.59 g) were added at 2 hour intervals. 2M hydrochloric acid (25 ml) was added and the organic layer was separated. The solution was washed with 2M hydrochloric acid (2×25 ml), water (25 ml) and saturated sodium chloride solution (25 ml) The solution was dried (MgSO4) and volatile material was removed by evaporation. The residue was recrystallised from isohexane to give isobutyl N-(5-chloro-3-methoxypyrazin-2-yl)carbamate (6.15 g), m.p. 90°-91° C.; microanalysis found: C, 46.3; H, 5.5; N, 16.4%; C10H14C1N3O3 requires: C, 46.3; H, 5.4; N, 16.2%.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].Cl.[OH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1
Reactant: C[Si](C)(C)Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 1.85 ml of chlorotrimethylsilane in 10 ml of CH2Cl2 is added dropwise to a solution of 2.0 g of trans-4-hydroxycyclohexylamine hydrochloride and 4.05 ml of triethylamine in 20 ml of CH2Cl2, cooled to 0° C. After stirring for 16 hours at room temperature, the mixture is hydrolyzed with water and extracted. The organic phase is washed successively with water, a 5% solution of Na2CO3 and saturated NaCl. After drying over MgSO4 and evaporation of the solvents, 1.43 g of amine (colorless liquid) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[C:20]1([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:15](=[O:17])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=3)[S:10][CH:11]=2)[CH2:30][CH2:29]1)(=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: O=C(c1ccccc1)N1CCNCC1
Product: O=C(Nc1nc(CC(=O)N2CCN(C(=O)c3ccccc3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with phenyl-piperazin-1-yl-methanone (CAS 13754-38-6) to give N-{4-[2-(4-benzoyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-4-chloro-benzamide, using general procedure C. White solid. MS 469.3 ([M+H]+)
Reaction SMILES: [SH:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[Na+].Br[CH2:13][N+:14]([O-:16])=[O:15]>CN(C=O)C.O>[N+:14]([C:13]1[S:1][C:2]2=[N:9][CH:8]=[CH:7][CH:6]=[C:3]2[C:4]=1[NH2:5])([O-:16])=[O:15]
Reactant: O=[N+]([O-])CBr
Reactant: N#Cc1cccnc1S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])sc2ncccc12
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a solution of 2-mercaptonicotinonitrile (1 g, 7.4 mmol) in DMF (20 mL) was added a solution of NaOH (0.88 g, 22 mmol) in water (5 mL) at 0° C. The mixture was stirred for 20 min, then bromonitromethane (2 g, 14.7 mmol) was added dropwise. The resulting mixture was stirred for 1 h at 0° C., diluted with water (100 mL), and filtered. The filter cake was washed with water (20 mL×3) to give a yellow solid (1.1 g, yield 78%), which was used in the next step without further purification. ESI MS: m/z 196 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:36]=[CH:35][C:18]([O:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@H:21]2[NH:29][C:30](OCC)=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CCCC1.C(O)C.C(Cl)(Cl)[Cl:46]>>[ClH:46].[CH2:7]([O:14][C:15]1[CH:36]=[CH:35][C:18]([O:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@H:21]2[NH:29][CH3:30])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Reactant: ClC(Cl)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN[C@@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Product: Cl
Temperature: 25 °C

Procedure:
The title compound was prepared in a similar manner to Example 12 from LiAlH4 (190 mg, 5 mmol), trans-1-(4-benzyloxyphenoxy)-2-ethoxycarbonylaminoindane (750 mg, 1.7 mmol) and tetrahydrofuran (50 ml). After a reaction time of 18 h at room temperature and a further hour at reflux, the reaction was worked up as previously described and subjected to column chromatography on silica gel eluting with 2% ethanol in chloroform to afford a pale yellow oil (290 mg) which was converted to the HCl salt and crystallised to afford the title compound as a white solid. m.p. 185°-187° C. (from methanol-diethyl ether).
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][C:9]3[C:16]([O:17]C)=[C:15]([O:19]C)[CH:14]=[CH:13][C:10]=32)[CH2:5]1)[CH3:3].B(Br)(Br)[Br:22].CO.CCOCC>C(Cl)Cl>[BrH:22].[CH2:2]([N:4]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][C:9]3[C:16]([OH:17])=[C:15]([OH:19])[CH:14]=[CH:13][C:10]=32)[CH2:5]1)[CH3:3]
Reactant: CCN1CC2CCc3c(ccc(OC)c3OC)C2C1
Reactant: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: Br
Product: CCN1CC2CCc3c(ccc(O)c3O)C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A solution of the compound of example 6 (1.1 g, 3.7 mmole) and 11 mL CH2Cl2 was stirred under N2 at -78° C. and a solution of BBr3 (1.08 mL, 11.5 mmole) in 3.5 mL CH2Cl2 was added dropwise. The reaction mixture was stirred for 1 hr at -78°, 2 hours at 0°, and 1 hour at room temperature. After cooling again to -78°, 20 mL MeOH was added dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight. Approximately 20 mL Et2O was added and the precipitate filtered, washed with 5% EtOH in Et2O, and dried (in-vacuo) to yield 0.8 g pale yellow solid; M+ 233; mp 223°-7°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Cc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(Br)cc2)nc1
Yield: 91.9 %

Procedure:
To a 500 mL round bottom flask, 4-bromophenylboronic acid (25.0 g, 0.125), 2-bromo-5-methylpyridine (20.0 g, 0.114 mol), palladium(0)tetrakistriphenylphosphine (4.0 g, 0.0035 mol), potassium carbonate (47.0 g, 0.34 mol.), 1,2-dimethoxyethane (120 mL) and water (120 mL.) were added. The mixture was heated to reflux under nitrogen atmosphere for 18 hours. After the reaction was cooled down, 100 mL of water and 150 mL of ethyl acetate were added. The mixture was separated in a separatory funnel. The organic phases were collected, combined and evaporated. The mixture was distilled using a kugelrohred (spelling?) to obtain 2-(4-bromophenyl)-5-methylpyridine (26.0 g) as a white solid that was further purified by recrystallization in hexanes.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[C:14]1[O:18][N:17]=[C:16]([CH3:19])[N:15]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>ClCCl>[CH3:12][N:5]1[C:6]2=[N:7][CH:8]=[CH:9][N:10]=[C:11]2[C:2]([O:1][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[C:3]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[N:15]=2)[C:4]1=[O:13]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1noc(-c2c(O)c3nccnc3n(C)c2=O)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1noc(-c2c(OC(=O)C(C)C)c3nccnc3n(C)c2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8-hydroxy-5-methyl-7-(3-methyl-1,2,4-oxadiazol-5-yl)-5H-pyrido[2,3-b]pyrazin-6-one (Example 7.4) (0.044 g) and pyridine (0.018 ml) in dichloromethane (1 ml) was added dropwise isobutyryl chloride (0.022 ml). The reaction mixture was stirred at ambient temperature for 4 hours and then stored at ambient temperature for 16 hours. The reaction mixture was diluted with more dichloromethane and the mixture was washed successively with aqueous sodium hydrogen carbonate (saturated), aqueous ammonium chloride (saturated) and brine. The organic fraction was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:1) to give Compound No. B6 of Table 6 as a pale yellow solid (0.020 g).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:18])[NH:6][N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[CH:11]=2)[CH:9]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:23]O>>[F:17][C:12]1[CH:11]=[C:10]([C:8]2[CH:9]=[C:4]([C:1]([O:3][CH3:23])=[O:2])[C:5](=[O:18])[NH:6][N:7]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: CO
Reactant: Cc1ccc(-c2cc(C(=O)O)c(=O)[nH]n2)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(C)c(F)c2)n[nH]c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To an ice-cold suspension of 4-carboxy-6-(3-fluoro-4-methylphenyl)-2H-pyridazin-3-one (5.50 g, 22.2 mmol) in methanol (100 mL) was added dropwise thionyl chloride (2.72 g, 24.4 mmol), and the mixture was stirred at 80° C. for 8 hours. The temperature of the reaction mixture was allowed to drop back to room temperature, and the solvent was distilled off under reduced pressure. Water was added to the ice-cold residue. The precipitate was collected by filtration, washed with water and dried to yield the title compound as pale yellow fine-needles (5.43 g, 92.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH3:18])([C:14](OC)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:19][CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][C:11]([CH2:14][OH:15])([CH3:18])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COC(=O)C1(C)CCN(c2ccc(Cl)c(OC)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(N2CCC(C)(CO)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
A solution of methyl 1-(4-chloro-3-methoxyphenyl)-4-methylpiperidine-4-carboxylate (500 mg, 1.679 mmol) in anhydrous THF (5 mL) and Et2O (10 mL) was treated dropwise with lithium aluminum hydride (3.36 mL of a 1.0 M solution in THF, 3.36 mmol) while the reaction temperature was controlled with a water bath. The mixture was then stirred at RT for 1 h, treated with Na2SO4.10H2O (1 g), stirred vigorously for 30 min and then dried with anhydrous MgSO4. The mixture was filtered and concentrated to give (1-(4-chloro-3-methoxyphenyl)-4-methylpiperidin-4-yl)methanol as a pale yellow oil (460 mg). The product was used without further purification in the subsequent step.