Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1)#[N:2].C(O)C.[OH-].[Na+]>O>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 60 °C
Yield: 82 %

Procedure:
A mixture containing ethyl p-cyanobenzoate (87.5 g, 0.5 mol), ethanol (192.5 g), and water (449.2 g) was placed in a 1 l-flask. The mixture was heated to 60° C., and a 20% aqueous solution of sodium hydroxide was added thereto so as to adjust the pH of the mixture at 9.9-10.0. Twenty-three hours after the reaction started, liquid chromatographic analysis revealed that the reaction mixture contained 60.3 g of p-cyanobenzoic acid (yield 82%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]2)[CH:18]=[CH:19][CH:20]=1.C(N(C(C)C)C(C)C)C.C(O)CCC>O.CCOC(C)=O>[F:14][C:15]1[CH:16]=[C:17]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(C2CCCCN2)c1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc2ccc(N3CCCCC3c3cccc(F)c3)nn12
Temperature: 180 °C
Reaction time: 24 h

Procedure:
To a pressure reaction tube were charged 6-chloro-3-nitroimidazo[1,2-b]pyridazine (450 mg, 2.27 mmol), 2-(3-fluorophenyl)piperidine (609 mg, 3.40 mmol, purchased from ChemBridge), and N-ethyl-N-isopropylpropan-2-amine (0.51 mL, 2.95 mmol), followed by addition of 1.0 mL n-butanol. The reaction mixture was then sealed and stirred at 180° C. for 24 hours. After completion, the reaction was cooled to ambient temperature, and diluted with water and EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc twice. The combined organic layers was dried over Na2SO4 and concentrated. The crude product was purified by silica column chromatography, eluting with 20 to 50% EtOAc in hexanes to yield the desired product for the next step.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:11]1.CC1(C)[C@@]23[C@@]4(ON4S(=O)(=[O:32])C2)C[C@H]1CC3.[Cl-].[NH4+]>O1CCCC1>[OH:32][CH:19]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH3:9])[CH:11]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC1(C)[C@@H]2CC[C@]13CS(=O)(=O)N1O[C@]13C2
Reactant: COC(=O)Cc1cn(C)c2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1cn(C)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of 2.87 millimole of LDA in 5 mL of dry tetrahydrofuran at -78° C. was added dropwise a solution of 0.53 g of methyl 2-(1-methyl-3-indolyl)acetate in 5 mL of dry tetrahyrofruan. The mixture was stirred for 30 minutes at -78° C., and then 0.9 g of (+)-(2R,8aS)-(camphorsulfonyl)oxaziridine was added. The mixture was warmed to room temperature and stirred for 2 hours. Then the mixture was poured into a solution of saturated aqueous ammonium chloride, and then extracted with diethyl ether. The ether extract was dried with magnesium sulfate and concentrated by evaporation. The residue was subjected to silica gel chromatography using a developing solution of dichloromethane/ethyl acetate (98:2 by volume) to give 0.38 g of an oily product.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[C:10]([OH:23])=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2.CCN(C(C)C)C(C)C>CS(C)=O.O>[OH:23][C:10]1[C:9]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=2)[N:11]=1
Reactant: C[C@H]1COCCN1
Reactant: COC(=O)c1ccc2nc(O)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(O)c(N3CCOC[C@@H]3C)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of (3S)-3-methylmorpholine (200 mg, 1.98 mmol) in DMSO (10 mL) was added methyl 3-chloro-2-hydroxyquinoxaline-6-carboxylate (700 mg, 2.93 mmol), DIEA (510 mg, 3.95 mmol). The resulting solution was stirred overnight at 70° C. and then dissolved in water (100 mL), extracted with dichloromethane (4×30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography with 5%˜50% ethyl acetate in petroleum ether to afford methyl 2-hydroxy-3-[(3S)-3-methylmorpholin-4-yl]quinoxaline-6-carboxylate as a light yellow solid (210.0 mg).
Reaction SMILES: Br[CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:4]([N:18]([CH3:20])[CH3:19])[O:3]1.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:4]([N:18]([CH3:20])[CH3:19])[O:3]1)[CH3:22]
Reactant: CCO
Reactant: CN(C)C1=C(c2cccc(C(F)(F)F)c2)C(=O)C(Br)O1
Product: CCOC1OC(N(C)C)=C(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In this example, 0.16 g of sodium was added to 10 ml of anhydrous ethanol at room temperature resulting in the formation sodium ethoxide. A solution containing 2.5 g of 2-bromo-3-oxo-4-(3-trifluoromethylphenyl)-5-dimethylamino-2,3-dihydrofuran in 10 ml of ethanol was slowly added and the resulting mixture stirred at room temperature for one hour. The mixture was then evaporated to remove solvent. The residue was dissolved in methylene chloride, washed with water, dried over magnesium sulfate evaporated yielding in oil residue. The residue was chromatographed eluting with tetrahydrofuran:chloroform mixtures. The produced fractions afforded 1 g of the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[O:32]([C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]O)[CH2:41][CH2:40]1)=[O:38])[C:33]([CH3:36])([CH3:35])[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:33]([O:32][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:36])([CH3:34])[CH3:35]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (600 mg, 2.0 mmol), as prepared in the preceding step, N-tert-butoxylcarbonyl4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step (b), and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and was extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 nmL) and dried over Na2SO4. The solvent removed in vacuo and the residue was purified by flash column chromatography (2:1 ethyl acetate/hexane) to give the title compound as a colorless syrup (895 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 1.24 (m, 2 H), 1.47 (s, 9 H), 1.76 (d, 2 H, J=6.6 Hz), 1.89 (m, 1 H), 2.24 (s, 3 H), 2.72 (t, 2 H, J=2.4 Hz), 3.68 (d, 2 H, J=3.2 Hz), 4.13 (m, 2 H), 6.47 (t, 1 H, J=2.2 Hz), 6.52 (d, 1 H, J=0.7 Hz), 6.58 (d, 1 H, J=0.8 Hz), 7.38 (dd, 1 H, J=0.6, 0.8 Hz), 7.61 (m, 2 H), and 7.97 (dd, 1 H, J=0.8,4.0 Hz).
Reaction SMILES: [OH-].[K+].I[CH3:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([SH:22])=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1>O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([S:22][CH3:4])=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1
Reactant: Fc1ccc(Cn2c(S)nc3cncnc32)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CSc1nc2cncnc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a stirred mixture of 4.6 parts of Potassium hydroxide and 200 parts of water were added portionwise 1.7 parts of iodomethane, followed by the dropwise addition of 3.8 parts of 9-[(4-fluorophenyl)methyl]-9H-purine-8-thiol. Upon complete addition, the whole was stirred for 2 hours at room temperature. The precipitated product was filtered off and dried, yielding 3.45 parts (73.9%) of 9-[(4-fluorophenyl)methyl]-8-(methylthio)-9H-purine; mp. 167.1° C. (interm. 25).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@:17]([CH3:29])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:31])[OH:30].Br.[Cl:33][C:34]1[N:39]=[CH:38][NH:37][C:36]2=[N:40][CH:41]=[CH:42][C:35]=12.[OH-].[K+]>CN1CCCC1=O.C1(C)C=CC=CC=1>[Cl:33][C:34]1[C:35]2[CH:42]=[CH:41][N:40]([C@@H:13]3[O:16][C@:17]([CH3:29])([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:31])[OH:30])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: CO[C@H]1O[C@](C)(COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: C[C@]1(O)[C@H](n2ccc3c(Cl)ncnc32)O[C@](C)(COCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To the compound from Step C (0.70 g, 1.3 mmol) was added HBr (5.7 M in acetic acid, 2 mL). The resulting solution was stirred at room temperature for 1 h, evaporated in vacuo and co-evaporated with anhydrous toluene (3×10 mL). 4-Chloro-1H-pyrrolo[2,3-d]pyrimidine (0.5 g, 3.3 mmol) and powdered KOH (85%, 150 mg, 2.3 mmol) were stirred in 1-methyl-2-pyrrolidinone (5 mL) for 30 min and the mixture was co-evaporated with toluene (10 mL). The resulting solution was poured into the above bromo sugar residue and the mixture was stirred overnight. The mixture was diluted with toluene (50 mL), washed with water (3×50 mL) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with (EtOAc/Hexane 15/85) to afford a solid (270 mg).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=3)=[O:33])[C:14]1=[O:42])=[O:11])[CH2:2]2.C(=O)([O-])[O-].Br[CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50].C(OCC)(=O)C>CN(C)C=O.O>[CH:5]12[CH2:6][CH2:7][CH:1]([CH2:9][CH2:8]1)[CH2:2][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:36]=3)=[O:33])[C:14]1=[O:42])=[O:11])[CH2:4]2
Reactant: O=C(Nc1cccc(O)c1)NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-hydroxyphenyl)urea, pottasium carbonate and ethyl bromoacetate in dimethylformamide was stirred at room temperature for 4 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The organic solvent was evaporated to dryness, and washed with isopropyl ether and vacuumed to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(ethoxycarbonylmethoxy)phenyl]urea.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[N:17]=3)=[CH:12][CH:11]=2)C(=O)C2=CC=CC=C12.O.NN>>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[N:17]=2)=[CH:12][CH:11]=1
Reactant: COc1cc(Nc2nccc(-c3ccc(OCCCN4C(=O)c5ccccc5C4=O)cc3)n2)cc(OC)c1OC
Agent: NN
Solvent: O
Product: COc1cc(Nc2nccc(-c3ccc(OCCCN)cc3)n2)cc(OC)c1OC
Yield: 10 %

Procedure:
The compound was prepared in a manner analogous to the preparation of the compound of Example 48 from the compound of Example 50 (830 mg, 1.54 mmol) and hydrazine monohydrate (0.23 ml, 4.62 mmol) to give the title compound (63 mg) as a white solid m.p. 161-162°. MS m/z 411(M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][CH2:25][C:26](Br)=[O:27]>>[Br:24][CH2:25][C:26]([N:12]1[C@@H:13]2[CH2:19][CH2:18][CH2:17][C@@H:14]2[C:15](=[O:16])[N:9]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]1=2)=[O:27]
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1CCc1ccccc1
Reactant: O=C(Br)CBr
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1CCc1ccccc1
Yield: 72 %

Procedure:
Employing (3aR*,10aS*)-9-(2-phenylethyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta-[e][1,4]diazepin-10(1H)-one and bromoacetyl bromide, the titled compound was synthesized by substantially the same procedure as in Working Example 185. Yield 72%. Oily product.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([N:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])=[N:25][C:24]=2[CH2:23]1)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)(C(C)(C)C)(C)C.Cl.CC(O)C>C(Cl)Cl>[Cl:18][C:13]1[CH:12]=[C:11]([C@H:10]([NH:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:38])[C:34]([F:36])([F:37])[F:35])=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][OH:8])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(Nc1ncc2c(n1)CN(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1)CC2)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(Nc1ncc2c(n1)CN(C(=O)N[C@H](CO)c1ccc(Cl)c(Cl)c1)CC2)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 302 (0.160 g, 0.270 mmol) and DCM (5 mL) at RT was added 6M HCl in IPA (0.450 mL, 2.70 mmol) and the reaction was stirred for 1 h. The reaction was poured into satd. aq. Na2CO3, and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:20 to 500:30) to afford 0.010 g (7.74%) of I-76: MS m/z (APCI-pos) M+1=478.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][C:8]([CH3:15])([CH2:13][CH3:14])[C:9](=[O:12])[CH2:10][Cl:11].CCCCCC.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Cl:33])[C:31]=1[CH3:32])[C:26](Cl)=[O:27]>O.O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Cl:33])[C:31]=1[CH3:32])[C:26]([NH:7][C:8]([CH2:13][CH3:14])([CH3:15])[C:9](=[O:12])[CH2:10][Cl:11])=[O:27]
Reactant: CCC(C)(N)C(=O)CCl
Reactant: Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(C)(NC(=O)c1cc(Cl)c(C)c(Cl)c1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a well-stirred solution of 1.1 g (13.1 mmol) sodium bicarbonate in 15 mL water was added solid 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride (1 g, 5.4 mmoles) portionwise. To the resulting solution was added 15 mL of hexane followed by dropwise addition of a solution of 3,5-dichloro-4-methylbenzoyl chloride (1.2 g, 5.4 mmol) in 1 mL of tetrahydrofuran. Another 15 mL of hexane was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the resulting white solid was dried in a vacuum oven yielding 1.1 g of 3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide as a white solid (mp 159-161° C.).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:19]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2cc(OC)ccc2C1=O
Solvent: CO
Product: COc1ccc2c(c1)CC(CC=O)C2=O
Reaction time: 1.42 h
Yield: 110.5 %

Procedure:
Ozone (3 g ozone/hour) was conducted while stirring for 85 minutes through a solution, cooled to -70°, of 19.2 g of (RS)-2-(2-buten-1-yl)-5-methoxy-1-indanone in 600 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen and then 9.1 ml of dimethyl sulfide were added to the cold solution. The solution came to room temperature overnight and was evaporated in a vacuum. The residue was chromatographed (dichloromethane) over a column with oxalic acid solution adsorbed on silica gel (600 g silica gel; 100 ml 10% oxalic acid solution). 14.1 g (78%) of (RS)-2-(2-oxoethyl)-5-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH2:19])([CH3:18])[CH3:17])=[CH:12][N:11]=1)(C(C)(C)C)(C)C>CC(O)=O.C1COCC1.O>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH2:19])([CH3:17])[CH3:18])=[CH:12][N:11]=1
Reactant: CC(C)(N)c1ccc(CO[Si](C)(C)C(C)(C)C)nc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(N)c1ccc(CO)nc1
Yield: 37.1 %

Procedure:
A solution of 1-[2-(tert-butyldimethylsilyloxymethyl)pyridin-5-yl](1-methyl)ethylamine (1.5 g, 5.35 mmol) in AcOH (15 ml), THF (5 ml) and H2O (5 ml) was heated at 50° C. for 2.5 h. The resultant mixture was concentrated under reduced pressue and then azeotroped with toluene (2×50 ml). The residue was dissolved in CH2Cl2 (15 ml) and MeOH (15 ml) and dry loaded onto silica. Purification by column chromatography on silica, using 10% MeOH/CH2Cl2 containing 1% NH3 solution as eluent, gave the desired alcohol (330 mg, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([NH:19][CH3:20])=[N:12][C:11]=2[O:21][CH2:22][CH:23]([F:25])[F:24])=[CH:4][CH:3]=1>[Ni].C1COCC1>[NH2:16][C:14]1[C:13]([NH:19][CH3:20])=[N:12][C:11]([O:21][CH2:22][CH:23]([F:25])[F:24])=[C:10]([CH:15]=1)[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:26]
Reactant: CNc1nc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CNc1nc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of N-(4-bromo-phenyl)-2-(2,2-difluoro-ethoxy)-6-methylamino-5-nitro-nicotinamide (150 mg, 0.35 mmol), THF (10 mL) and Ra—Ni (15 mg) is stirred for 6 h at rt under a hydrogen atmosphere (3.0 bar). The catalyst is removed by filtration and the filtrate is concentrated to give the sub-title compound.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([Si:17]([CH3:27])([CH3:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][C:7]([O:9]CC1C=CC=CC=1)=[O:8])([O-])=O>CO.[OH-].[Pd+2].[OH-]>[NH2:1][CH2:4][CH:5]([Si:17]([CH3:26])([CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCCCCCC[Si](C)(C)C(CC(=O)OCc1ccccc1)C[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCC[Si](C)(C)C(CN)CC(=O)O

Procedure:
A suspension of benzyl 4-nitro-3-(dimethyl-n-octylsilyl)butanoate (220 mg, 0.560 mmol) and palladium hydroxide (20% on carbon, wetted with ca. 50% water, 44 mg) in methanol (2 ml) was subjected to catalytic reduction under a hydrogen atmosphere [0.25 MPa (gauge pressure)] for 48 hours. After the suspension was filtered through Celite, and the solvent was evaporated, the residue was washed with water and recrystallized to obtain 4-amino-3-(dimethyl-n-octylsilyl)butanoic acid mentioned in the title.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].N1C=CC=CC=1.[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=1)([CH3:21])[CH2:19][OH:20])([CH3:14])([CH3:13])[CH3:12].Cl>C(Cl)Cl>[C:11]([O:15][C:16]([N:17]1[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=2)([CH3:21])[CH2:19][O:20][S:1]1=[O:2])=[O:29])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1cccc(Br)n1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an at 0° C. precooled solution of thionyl chloride (3.42 ml, 5.57 g, 46.8 mmol) in pyridine (9.46 ml, 9.25 g, 117.0 mmol) was added dropwise a solution of [1-(6-bromo-pyridin-2-yl)-2-hydroxy-1-methyl-ethyl]-carbamic acid tert-butyl ester (see Example 1 step d), 7.75 g, 23.4 mmol) in DCM (230 ml). The reaction mixture was allowed to stir for 1 h at rt, then 0.5 N aq. HCl and DCM were added, the phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated to leave the title compound (mixture of diastereomers) as an orange solid. HPLC RtH4=1.16, 1.20 min (diastereomers); ESIMS: 377, 379 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[F:16])\[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[F:16])\[CH2:7][Br:18])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(F)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(F)c1F
Yield: 39.6 %

Procedure:
To a stirred mixture of (E)-3-(2,3-difluoro-phenoxy)-but-2-enoic acid ethyl ester (8.01 g, 0.033 mol) in carbon tetrachloride (30 mL) under a nitrogen atmosphere was added N-bromosuccinimide (8.91 g, 0.050 mol) and benzoyl peroxide (810 mg, 0.003 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2,3-difluoro-phenoxy)-but-2-enoic acid ethyl ester (4.20 g, 40%) as a yellow oil.