Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>O>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:1]=[O:3])=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: Nc1ccc(Br)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of formic acid (2.5 mL, 88% in water) is cooled to 0° C., treated with acetic anhydride (0.82 mL, 9.0 mmol) then warmed to RT over 30 minutes. The solution is then cooled to 0° C. and 4-bromoaniline (500 mg, 3.0 mmol) added dropwise over 5 minutes. After stirring a further 16 h at RT, the reaction mixture is diluted with water (20 mL) and extracted into DCM (3×20 mL). The combined DCM phases are washed with 1 M HCl (20 mL) and aqueous NaHCO3 (20 mL), dried over Na2SO4 and reduced in vacuo. Purification by column chromatography (20% EtOAc in heptane) affords the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([O:14][CH3:15])[CH2:9]2)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([O:14][CH3:15])[CH2:9]2
Reactant: CON1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CCO
Product: CON1Cc2cccc(N)c2C1=O
Yield: 84.2 %

Procedure:
A solution of 7-nitro-2-methoxy-2,3-dihydro-1H-isoindol-1-one (Compound 187B, 0.25 g, 1.2 mmol) in ethanol (5 mL) was hydrogenated over 5% Pd/C (30 mg) overnight at room temperature. The catalyst was filtered off by a glass filter paper and the filtrate was concentrated to give 0.18 g of the pure product (yield: 85%). 1H NMR (CDCl3, 600 MHz): δ=3.93 (s, 3 H), 4.48 (s, 2 H), 6.56 (d, J=8.5 Hz, 1 H) 6.63 (d, J=7.0 Hz, 1 H), 7.24 (dd, J=7.5, 8.5 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[I:13]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([S:11][CH3:12])=[N:9][C:10]=2[I:13])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CSc1ncc2c(Cl)nccn12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(I)c2c(Cl)nccn12
Temperature: 55 °C
Reaction time: 6 h

Procedure:
To a solution of 8-chloro-3-methylsulfanyl-imidazo[1,5-a]pyrazine (1.75 g, 0.00876 mol) in DMF (15 mL) was added N-iodosuccinimide (3.94 g, 0.0175 mol), the resulting mixture was stirred at 55° C. for 6 h. The mixture was diluted with EtOAc (200 mL), washed with sat. aq. NaHCO3 (40 mL), water (2×40 mL), brine (40 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography to give the title compound as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.72 (s, 3H), 7.36 (d, J=4.8 Hz, 1H), 7.76 (d, J=4.8 Hz, 1H).
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].CS[C:7]1[N:12]([NH2:13])[C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1.CI>CO>[CH3:2][O:3][C:7]1[N:12]([NH2:13])[C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1
Reactant: C[O-]
Reactant: CSc1nnc(-c2ccccc2)c(=O)n1N
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: CO
Product: COc1nnc(-c2ccccc2)c(=O)n1N
Reaction time: 1 h

Procedure:
2.3 g sodium are added to 500 ml methanol whereby a sodium methylate solution is formed. 23.4g 3-methylthio-4-amino-6-phenyl-1,2,4-triazine-5-one (1a) and 6.5 ml methyl iodide are added. The mixture is boiled for one hour. When cooling down the mixture, a crystalline precipitate separates. The crystals are removed by suction and recrystallized from methanol and optionally once more from acetic acid ester. The 3-methoxy-4-amino-6-phenyl-1,2,4-triazin-5-one (33") thus obtained has a melting point of 167°C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]23[CH2:18][C:15]([C:19]([OH:21])=O)([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[O:9])[CH:5]=[N:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]23[CH2:18][C:15]([C:19]([NH:28][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)=[O:21])([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(C(=O)NC23CCCC(C(=O)O)(CC2)C3)n1
Reactant: Nc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(C(=O)NC23CCCC(C(=O)Nc4ccccn4)(CC2)C3)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
To a solution of 5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylic acid (intermediate 26, 100 mg, 0.35 mmol) and pyridin-2-amine (39 mg, 0.41 mmol) in DMF (5 mL) was added HATU (158 mg, 0.41 mmol) and DIPEA (0.5 mL). After stirring at room temperature for one hour, water (20 mL) was added, and the solution was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate: 2/1) to yield 35 mg (27%) of 6-methyl-N-{5-[(pyridin-2-ylamino)carbonyl]bicyclo[3.2.1]oct-1-yl}pyrazine-2-carboxamide as a white solid. Analytical data were listed in Table 3.
Reaction SMILES: [N+](=[CH:3][CH3:4])=[N-].[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH:18]([S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][C:15]1=[O:27])([OH:7])=[O:6].C(O)C.Cl>CCOCC>[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH:18]([S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][C:15]1=[O:27])([O:7][CH2:3][CH3:4])=[O:6]
Reactant: CC=[N+]=[N-]
Reactant: CCCCCCCSC1CCC(=O)C1CCCCCCC(=O)O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCCCCCSC1CCC(=O)C1CCCCCCC(=O)OCC
Temperature: 0 °C

Procedure:
At room temperature, 70 ml. of a 0.2N diazoethane solution in ether is added to a solution of 3.4 g. of 2-(6-carboxyhexyl)-3-heptylthio-cyclopentanone in 25 ml. of dry ethanol. The reaction mixture is poured into 100 ml. of ice water, containing 5 ml. of concentrated HCl, agitated, the organic phase separated, the aqueous phase extracted three times with respectively 30 ml. of chloroform, and the combined organic phases are washed with water, dried over Na2SO4, the solvent is distilled off, and chromatographic purification of the residue (silica gel/chloroform) produces 2-(6-carbethoxyhexyl)-3-heptylthio-cyclopentanone. Rf = 0.7 (silica gel/chloroform).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.C(#N)C>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.7 %

Procedure:
A solution of sodium hydroxide (0.63 g) in a mixture of water:acetonitrile (60:40 v/v, 19 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:acetonitrile (60:40 v/v, 106 ml) at reflux temperature. The solution was heated at reflux temperature for an additional 1 hour. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. Seeding was done, and the reaction mixture was stirred at 10° C. for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetonitrile (2×10 ml), and dried in a vacuum oven at 50° C. for 23 hours to obtain 1.0 g of ibandronate sodium crystal form Q.
Reaction SMILES: [Br:1][C:2]1[N:7]2[C:8]([CH3:11])=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[O:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[N:7]2[C:8]([CH3:11])=[CH:9][N:10]=[C:6]2[C:5]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)=[CH:25][CH:24]=2)=[N:4][CH:3]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1cnc2c(Br)ncc(Br)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc2c(Nc3ccc(N4CCOCC4)cc3)ncc(Br)n12
Yield: 52.6 %

Procedure:
5,8-Dibromo-3-methylimidazo[1,2-a]pyrazine (270 mg, 0.93 mmol) and 4-morpholinoaniline (200 mg, 1.1 mmol) are combined in nBuOH (10 mL) and DIPEA (240 μL, 1.4 mmol) is added. The mixture is heated at reflux for 10 h, cooled and the solvent removed under reduced pressure. The residue is purified by silica chromatography, eluting with 12%-100% EtOAc in cyclohexane, to afford the title compound as a red-brown solid (190 mg).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30](S(C)(=O)=O)[N:29]=1>O1CCCC1>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:30]1[N:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:28]([O:27][CH3:26])[N:29]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)Cc1ccccc1C
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(c1nc(OC)cc(OC)n1)c1ccccc1C
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
n-Butyllithium (10 ml of 2N solution in pentane) was added dropwise to a stirred solution of di-isopropylamine (2.0 g) in dry tetrahydrofuran (40 ml) under nitrogen at -10° C. After stirring at this temperature for 15 minutes, the solution was cooled to -75° C., and a solution of ethyl (2-methylphenyl)acetate (3.56 g) in tetrahydrofuran (20 ml) was added dropwise. After stirring at -75° C. for one hour, 4,6-dimethoxy-2-(methylsulphonyl)pyrimidine (4.36 g) was added in one portion, and the resulting suspension was allowed to warm slowly to room temperature before stirring overnight. The reaction mixture was then poured onto water (400 ml) and the resulting oil was extracted into ether (2×150 ml). The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated to give a yellow oil which was purified by chromatography to give 3.8 g of the desired product as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([NH2:15])[CH:14]=2)[O:3]1.[C:20]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)(=[O:22])[CH3:21].C(NC1C=CC(C(O)=O)=CC=1)(=O)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:20]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:15][C:13]2[CH:14]=[C:9]([B:4]3[O:3][C:2]([CH3:19])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=[CH:11][C:12]=2[N+:16]([O-:18])=[O:17])=[O:29])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c(N)c2)OC1(C)C
Agent: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a solution of compound 132 (18 mg, 0.689 mmol) in pyridine (2.8 mL) was added 4-acetamidobenzoyl chloride (150 mg, 0.758 mmol) and 4-(dimethylamino)pyridine (8 mg, 0.07 mmol) and the mixture was stirred for 16 h. at r.t. Then, it was partitioned between EtOAc and H2O, The aqueous layer was extracted with fresh EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude oil was purified by flash chromatography on silica gel using methanol/EtOAc (5:95) as the eluent affording the title compound 133 (47 mg, 16% yield) as a 1:1 mixture with 4-acetamidobenzoic acid (hydrolyzed starting material). 1H NMR: (Acetone-d6) δ(ppm): 10.76 (bs, 1H), 9.52 (bs, 1H), 9.00 (d, J=1.0 Hz, 1H), 8.20 (d, J=7.2 Hz, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.85 (d, J=8.6 Hz, 2H), 7.64 (dd, J=8.2, 1.2 Hz, 1H), 2.15 (s, 3H), 1.40 (s, 12H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrC/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24]/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:52][CH3:53])([CH2:54][CH3:55])[CH2:50][CH3:51])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(/C=C\CBr)(CC)O[Si](CC)(CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(/C=C\CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 59.8 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (33.0 mg, 0.0568 mmol), (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (91.0 mg, 0.284 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, hexane:ethyl acetate=2:1, developed once) to give the title compound as a pale yellow oil (23.8 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]([NH2:49])[CH3:48])=[CH:43][CH:42]=1>C1COCC1>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:49][C@H:47]([C:44]2[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=2)[CH3:48])=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(O)[C@H]1COCCN1c1nc(Cl)ncc1Br
Reactant: C[C@H](N)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C[C@H](NC(=O)C1COCCN1c1nc(Cl)ncc1Br)c1ccc(Cl)cc1
Yield: 72.2 %

Procedure:
To a 50 mL round-bottom flask were added (R)-4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (460 mg, 1.426 mmol), 1-hydroxybenzotriazole (193 mg, 1.426 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (328 mg, 1.711 mmol) in THF (10 mL) to give a beige solution. After 5 minutes (S)-1-(4-chlorophenyl)ethylamine (0.220 mL, 1.569 mmol) was added to the solution, which was allowed to react at room temperature for 1.5 hours. The reaction mixture was subsequently partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by normal phase column chromatography (20-50% EtOAc gradient in hexanes over 20 minutes) to give a diastereomeric mixture of the title compound as a white foam (474 mg, 72.2%). 1H NMR (400 MHz, DMSO-d6) δ 1.35-1.42 (m, 3H), 3.50-3.63 (m, 2H), 3.69-3.79 (m, 1H), 3.83-3.93 (m, 1H), 4.23-4.39 (m, 2H), 4.85-4.89 (m, 1H), 4.90-5.03 (m, 1H), 7.33-7.41 (m, 4H), 8.44-8.48 (m, 1H), 8.48-8.57 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C17H17BrCl2N4O2, 458.99; found 459.3.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[CH3:19][C@H:20]([C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[C:21](Cl)=[O:22]>C1COCC1>[CH2:17]([O:16][C:13](=[O:15])[CH2:14][C:21](=[O:22])[C@H:20]([CH3:19])[C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[CH3:18]
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC[C@@H](C)[C@@H](C)C(=O)CC(=O)OCC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution containing 2.0 g (13.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 20 mL of dichloromethane was added 2.1 g (16.6 mmol) of chloromethylene dimethyl-ammonium chloride. After stirring the resulting solution under nitrogen for 1.5 hours, the solvent was evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. Butyl lithium (32.7 ml, 52.4 mmol) was added to a solution of diisopropylamine (4.9 g, 48.5 mmol) in dry THF (20 mL) under nitrogen at 0° C. and stirred for 20 minutes. The solution was cooled to −78° C. and 4.3 g (48.5 mmol) of ethyl acetate was added. The solution was stirred at that temperature for 45 minutes. (2R,3R)-2,3-Dimethyl-hexanoyl chloride in dry THF (20 mL) was slowly added to the ethyl acetate enolate at −78° C. and the resulting reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and was cooled to 0° C. The reaction was quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 2.7 g (89.2% yield) of the titled compound as an oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[C:12]([F:22])=[C:13]3[C:18](=[CH:19][C:20]=2[F:21])[N:17]=[CH:16][CH:15]=[CH:14]3)[CH3:10])[C:5]([NH2:23])=[N:4][CH:3]=1.[N:24]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:9]([C:11]3[C:12]([F:22])=[C:13]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]=[CH:16][CH:15]=[CH:14]4)[CH3:10])[N:24]=[N:23][C:5]2=[N:4][CH:3]=1
Reactant: CC(Nc1nc(Br)cnc1N)c1c(F)cc2ncccc2c1F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(c1c(F)cc2ncccc2c1F)n1nnc2ncc(Br)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 6-bromo-N2-(1-(5,7-difluoroquinolin-6-yl)ethyl)pyrazine-2,3-diamine (450 mg, 1.2 mmol) in acetic acid (12 mL) was added a solution of sodium nitrite (82.0 mg, 1.2 mmol) in water (2 mL). After stirring at rt for 2 hours, the solvent was removed in vacuo. The residue was diluted with NaHCO3 (aq.), extracted with DCM. The organic layer was separated and washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellow solid (423 mg, 91%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.01 (dd, 1H), 8.95 (s, 1H), 8.52 (d, 1H), 7.75 (d, 1H), 7.64 (dd, 1H), 6.77 (q, 1H), 2.30 (d, 3H). LCMS (method A): [MH]+=391/393, tR=5.59 min.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.N1CCCCC1.[C:37]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[ClH:11].[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:46]2[CH2:47][CH2:48][CH:43]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:44][CH2:45]2)=[C:7]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)[CH:6]=1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: C1CCNCC1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCC(c3ccccc3)CC2)cc(OC)c1
Product: Cl

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl)-5-chloropentan-1-one and piperidine with 4-phenylpiperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-(4-phenylpiperidin-1-yl)pentan-1-one hydrochloride, m.p. 237°-239 C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1.O>CC(C)=O>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-hydroxy-5-nitrobenzoate (0.685 g, 3.5 mmol) was dissolved in acetone (75 mL). Potassium carbonate (1.43 g, 10.4 mmol) and 2-bromomethylnaphthalene (0.77 g, 3.5 mmol) were added, and the whole was stirred under reflux for 5 h. Mixture was cooled to room temperature and poured into basic (NaOH, pH 10-11) water. After 1 h, precipitated solid was filtered, washed with water (3×25 mL), and air-dried. Off-white crystals, yield 0.970 g (82%). 1H NMR (DMSO-d6, 400 MHz), δ: 8.24 (s, 1H); 8.14 (s, 1H); 8.05 (s, 1H); 7.99-7.90 (m, 4H); 7.63 (d, J=7.5 Hz, 1H); 7.57-7.50 (m, 2H); 5.51 (s, 2H); 3.92 (s, 3H).
Reaction SMILES: [CH:1](=[CH:8]/[C:9](=[O:11])[CH3:10])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.O.O1CCO[CH2:19][CH2:18]1>CCCCCC>[C:2]1([CH:1]([CH2:18][CH3:19])[CH2:8][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: CC(=O)/C=C/c1ccccc1
Agent: C[Al](C)C
Solvent: O
Solvent: CCCCCC
Product: CCC(CC(C)=O)c1ccccc1
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
143 mg of CuBr is added to 1.46 g (10 mmol) of cis/trans-benzylideneacetone (3-phenyl-but-3-en-2-one) in 20 ml of absolute dioxane. 11 ml (11 mmol) of a 1 molar solution of trimethyl aluminum in hexane is added to the reaction at room temperature under nitrogen atmosphere and, after completion of the addition, stirred for 10 minutes at 22° C. For hydrolysis of the reaction solution, 1 ml of water dissolved in 5 ml of dioxane is carefully added to the reaction. It is stirred for 10 minutes more and the inorganic precipitate filtered off with dioxane is washed again. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 1.37 g of 4-phenyl-hexan-2-one (78% of theory) is obtained a colorless liquid.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:8])[CH2:6][OH:7].CS([C:13]1[N:17]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16]2[CH:26]=[CH:27][C:28]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][OH:39])=[CH:34][CH:33]=3)=[CH:29][C:15]=2[N:14]=1)(=O)=O>C1COCC1.C(#N)C>[OH:39][CH2:38][C:35]1[CH:36]=[CH:37][C:32]([C:31]#[C:30][C:28]2[CH:27]=[CH:26][C:16]3[N:17]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:13]([O:7][CH2:6][C:5]([OH:4])=[O:8])=[N:14][C:15]=3[CH:29]=2)=[CH:33][CH:34]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(C#Cc3ccc(CO)cc3)ccc21
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c(OCC(=O)O)nc2cc(C#Cc3ccc(CO)cc3)ccc21
Reaction time: 0.08 h

Procedure:
A 20 mL scintillation vial equipped with a septum cap and a magnetic stirring bar was charged under N2 with NaH (12.0 mg, 60% suspension in mineral oil, 0.30 mmol). A solution of hydroxyacetic acid methyl ester (54.0 mg, 0.60 mmol) in THF (1.0 mL) was added dropwise to the vial. Immediately after the addition was complete, a solution of {4-[2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-5-ylethynyl]-phenyl}-methanol (compound 47-1, 49.1 mg, 0.100 mmol) in THF (1 mL) was added. The resulting yellowish suspension was stirred at it for 5 min, then diluted with ACN (2 mL) and quenched by addition of water (2 mL). The resulting solution was stirred at it for 5 min, then an additional 15 min at 65° C. The solution was acidified with 5% aqueous HCl and extracted with EtOAc (three times, 3 mL). The organic layers were combined and washed with 5% aqueous HCl and water and evaporated to dryness in vacuo to give the crude product as yellowish solid. LR-MS (APT-ES): mixture of two N-SEM isomers, calculated for C24H27ClN2O5Si 486.2, observed m/e 487.0 (M+H)+ (Rt 3.09, 3.20 min). The crude product was used in the next step without further purification.