Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:29])[CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=2)[CH2:9]/[C:10](=[N:31]\[OH:32])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(CC(=O)O)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(CC(=O)O)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-2-(4-(1-(4-chloro-2-methylphenyl)-3-(2-methylpyridin-4-yl)-3-oxopropyl)phenyl)acetic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white solid, MS (ESI+): m/z=423.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH2:11][CH2:10][CH2:9]1.[C:26]([C@@](C([O-])=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C([O-])=O)(=O)C1C=CC=CC=1.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][N:13]2[CH3:26])[CH2:9][CH2:10][CH2:11]1
Reactant: O=C([O-])[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)[O-])C(=O)c1ccccc1
Reactant: COc1cc2c(cc1OC)C(C1(c3ccccc3Br)CCC1)NCC2
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc2c(cc1OC)C(C1(c3ccccc3Br)CCC1)N(C)CC2
Reaction time: 0.25 h

Procedure:
A mixture of (-)-1-[1-(2-bromophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.85 g) [liberated from the dibenzoyl-(L)-tartrate salt (3.7 g)], acetonitrile (60 ml), 37-40% aqueous formaldehyde solution (1.8 ml) and sodium cyanoborohydride (0.46 g) was stirred for 15 minutes, then neutralised with glacial acetic acid and stirred for a further 45 minutes. The mixture was concentrated by evaporation and basified to pH 12 with dilute aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, the extract yielding a gum which was purified via flash chromatography using a 1:2 mixture of ethyl acetate and petroleum ether as eluant to give (-)-1-[1-(2-bromophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline, which had a specific optical rotation αD of -33.6°. Yield 1.6 g.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].CCN(CC)CC.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[N:5]=[C:18]=[O:20])[CH3:2]
Reactant: CCc1ccccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1N=C=O

Procedure:
The compound was prepared substantially in accordance with the procedure detailed in Example 27A, using 2-ethylaniline (1.5 ml, 12.2 mmol), Et3N (4.3 ml, 30.4 mmol) and triphosgene (1.2 g, 4.0 mmol) in 45 ml of CH2Cl2.
Reaction SMILES: F[C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([O:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])[CH:8]=1)=[O:5].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CCOC(C)=O>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:2]2[N:28]=[CH:27][CH:26]=[CH:25][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:10]=[C:9]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[CH3:24])[CH:8]=2)=[O:5])=[CH:32][CH:31]=1
Reactant: NCc1ccc(F)cc1
Reactant: CN1CCCC1COc1cc(NC(=O)c2cccnc2F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: CN1CCC[C@H]1COc1cc(NC(=O)c2cccnc2NCc2ccc(F)cc2)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
2-Fluoro-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide (300 mg), TEA (314 μL) and 4-fluorobenzylamine (170 μL) were combined in a sealed tube and heated to 90° C. for 3 h. Cooled to RT and the mixture was diluted with EtOAc, washed with sat. NH4Cl (2×), brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/MeOH/NH4OH 95/5/0.5) to provide an off-white foam upon drying. M+H 503. Calc'd for C26H26F4N4O2: 502.20.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:16])[NH:11]2.[I-].[Na+].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.CN(C)C=O.CC(C)=O>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C:10](=[O:16])[NH:11]3)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCc2c(cccc2OCCCCl)N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCc2c(cccc2OCCCN2CCN(Cc3ccccc3)CC2)N1
Reaction time: 7 h
Yield: 84.2 %

Procedure:
24 grams of 5-(3-chloropropoxy)-3,4-dihydrocarbostyril and 17 g of sodium iodide are mixed with 300 ml of acetone and heated for 3 hours under refluxing conditions. Then, 300 ml of dimethylformamide, 12 g of triethylamine and 18 g of 4-benzylpiperazine are added thereto and the reaction is carried out at 60°-70° C. for 7 hours under stirring conditions. The reactions mixture is concentrated under a reduced pressure to obtain a viscous liquid, then 300 ml of 3% sodium hydrogencarbonate aqueous solution are added. The organic layer is extracted with chloroform and washed with water. After drying the chloroform layer, chloroform is removed by distillation. The residue thus obtained is washed with ether and recrystallized from methanol to obtain 32 g (yield: 84%) of 5-[3-(4-benzylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 157°-159° C.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH3:5])=O.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(Br)(CC)C.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[OH:30])[O:26][C:25]([CH3:32])([CH3:31])[CH2:24][C:23]2=[O:33]>>[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH:2]([CH2:4][CH3:5])[CH3:1])[O:26][C:25]([CH3:31])([CH3:32])[CH2:24][C:23]2=[O:33]
Reactant: CC1(C)CC(=O)c2cc(O)c(O)cc2O1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)Br
Product: CCC(C)Oc1cc2c(cc1O)C(=O)CC(C)(C)O2
Reaction time: 12 h
Yield: 86 %

Procedure:
In 100 ml of methyl-ethyl-ketone 4.2 g (20 millimoles) of 6,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved and to the solution thus obtained 4.1 g (30 millimoles) of potassium carbonate, 0.5 g of potassium iodide and 3.3 g (2.6 millimoles, 24 millimoles) of sec. butyl bromide are added under stirring. The reaction mixture is heated to boiling for 12 hours. The reaction mixture is worked up according to Example 17. Thus 4.5 g of the desired compound are obtained, yield 86%, mp.: 114°-116° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][C:10]2([CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][C:10]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)CC(C)(C)O2
Agent: Cl
Solvent: CCO
Product: CC1(C)CN(Cc2ccccc2)CC2(CCNCC2)O1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To tert-butyl 2-benzyl-4,4-dimethyl-5-oxa-2,9-diazaspiro[5.5]undecane-9-carboxylate (560 mg, 1.50 mmol) was added hydrogen chloride (7.5 mL of 4 M in dioxane, 29.90 mmol), followed by ethanol (2 mL) and the reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo, dissolved in water (5 mL), washed with methyl tert-butyl ether (5 mL), basified with solid NaHCO3 then adjusted to pH 13-14 with 50% aq. NaOH. The aqueous layer was extracted with ethyl acetate (3×25 mL), dried over MgSO4 and concentrated to give 2-benzyl-4,4-dimethyl-5-oxa-2,9-diazaspiro[5.5]undecane (400 mg, 98%) as a yellow oil, which was used directly without further purification. ESI-MS m/z calc. 274.4. found 275.5 (M+1)+; Retention time: 0.75 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=3)[CH:18]([CH3:20])[CH3:19])=[C:14]([CH3:38])[C:13]=2[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=3)[CH:18]([CH3:20])[CH3:19])=[C:14]([CH3:38])[C:13]=2[CH:39]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCc4ccccc4)cc3c2C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C(C)C)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Ethyl 3-({[4-({1-[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)phenyl]carbonyl}amino)propanoate (0.43 g) synthesized in the above-mentioned (1) was dissolved in ethanol (10 mL), 1N aqueous sodium hydroxide solution (2.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (2.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.36 g, 89%) as a colorless solid.
Reaction SMILES: C(O)(=O)C.[CH:5]1([C:11]2[CH:12]=[C:13]([S:19]([NH:22][C@H:23]([C:31]([N:33]3[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH:34]3[C:40]([O:42]CC)=[O:41])=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(O)C.C(Cl)(Cl)Cl>[CH:5]1([C:11]2[CH:12]=[C:13]([S:19]([NH:22][C@H:23]([C:31]([N:33]3[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH:34]3[C:40]([OH:42])=[O:41])=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:30])(=[O:20])=[O:21])[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)C1CC(C)CCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc(OC)c(C2CCCCC2)c1
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N2CCC(C)CC2C(=O)O)cc1C1CCCCC1
Yield: 73.4 %

Procedure:
A solution of 2.4 g of ethyl 1-[N2 -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate acetate in 10 ml of ethanol and 10 ml of N-NaOH solution was stirred overnight at room temperature. Then, the reaction mixture was concentrated and dissolved in 10 ml of water. The solution was neutralized with 2N-HCl solution to give a white gummy precipitate which was dissolved in 150 ml of chloroform. The chloroform solution was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.52 g of 1-[N2 -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid as an amorphous solid. I.R. (KBr): 3350, 2920, 1620, 1250 cm-1.
Reaction SMILES: ClCCl.[CH2:4]([C@H:6]1[O:8][CH2:7]1)[Cl:5].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OC)(C)(C)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Cl:5][CH2:4][C@@H:6]([OH:8])[CH2:7][O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: ClC[C@@H]1CO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O[C@H](CCl)COc1ccccc1
Reaction time: 1 h
Yield: 115.8 %

Procedure:
To a mixture of N′,N′-disalicylidene ethylenediaminatocobalt(II) (173 mg, 0.532 mmol) and dichloromethane (13 ml) was added (±) camphorsulfonic acid (148 mg, 0.638 mmol) and the reaction system was stirred for 1 hour while being filled with air. The reaction solution was evaporated to dryness under reduced pressure to give a crude blackish (dark) brown cobalt (III) complex. Thereto was added tert-butylmethyl ether (5 ml) to disperse the crude cobalt (III) complex and then thereto were added (S)-epichlorohydrin (2.50 ml, 31.9 mmol, optical purity 99% e.e.) and phenol (2.50 g, 26.6 mmol) in order. The mixture was stirred for 24 hours under nitrogen atmosphere at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (20 ml), the solution was washed with a 6% aqueous sodium hydroxide solution (10 ml) and a saturated sodium chloride solution (10 ml) in order, and the organic layer was condensed under reduced pressure to give crude (S)-1-chloro-3-phenoxy-2-propanol (5.75 g). This crude compound (5.75 g) was dissolved in isopropanol (10 ml) and thereto was added a 24% aqueous sodium hydroxide solution (6.64 g, 39.8 mmol) under ice-cooling. The mixture was stirred for 1 hour at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (50 ml) and the solution was washed with water (20 ml), a saturated aqueous ammonium solution (20 ml) and a saturated aqueous sodium chloride solution (20 mm) in order. The organic layer was condensed under reduced pressure to give (R)-glycidylphenyl ether (3.96 g). Quantitative analysis by gas chromatography and optical purity measurement by HLPC were conducted on the compound. As a result the subject compound, (R)-glycidylphenyl ether (3.80 g, 95.4%) was produced with optical purity at 99% e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:28]([O:30]C)=[O:29])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1COCC1.O.[OH-].[Li+]>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:28]([OH:30])=[O:29])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, (2S,4R)-methyl 1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxylate (1.5 g, 3.11 mmol, Eq: 1.00) was combined with THF (20 ml) to give a light yellow solution. Then lithium hydroxide monohydrate (196 mg, 4.66 mmol, Eq: 1.5) in 4 ml water and 4 ml methanol was added. The reaction was stirred for 2 h at RT. The solvents were evaporated. The reaction was extracted with ethyl acetate, H2O and brine. The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a white foam (1.52 g, 97.1%, MS (m/e)=468.2 [M+H+]; MS (m/e)=466.1 [M−H+]).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].C1N2CN3CN(C2)C[N:13]1C3.Cl>C1(C)C=CC=CC=1.C(O)C>[NH2:13][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: NCC(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
To a stirred solution of 2-bromo-1-(4-bromophenyl)ethanone (130 g 0.478 mol) in toluene (2500 mL) was added hexamethylenetetramine (65.6 g 0.478 mol). The mixture was stirred at 40° C. for 16 hrs. The resulting solid was filtered off and washed with toluene and ether to give a white solid. To a stirred suspension of this white solid in ethanol (800 mL) was added concentrated hydrochloride acid (300 mL). The mixture was stirred at ambient temperature for 20 hrs. The solid was collected by filtration and washed with ethanol and water and dried in vacuo to give 2-amino-1-(4-bromophenyl)ethanone (4) (95 g, yield: 92%) as a white solid, which was used without purification for the next step. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.58 (s, br, 2H), 7.96 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 4.48-4.52 (m, 2H). ES LC-MS m/z=214, 216 (M+H)+.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:14]([O:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:25]=2[C:26]([OH:28])=O)=[CH:20][CH:19]=1)(=[O:16])[CH3:15].O.[OH-].[Na+]>C(Cl)Cl>[C:14]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:22][CH2:23][C:24]3[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:25]=3[C:26](=[O:28])[C:35]=2[CH:36]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Oc1ccc(OCc2cc(C#N)ccc2C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)Oc1ccc2c(c1)C(=O)c1ccc(C#N)cc1CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
3 ml of trifluoroacetic anhydride and 0.48 g of a trifluoroboran-diethyl ether complex were added to 5.36 g of 2-(4-acetoxyphenoxy)methyl-4-cyanobenzoic acid obtained in Reference example 24 dissolved in 80 ml of methylene chloride and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, the mixture was neutralized with a 1N-sodium hydroxide aqueous solution and crystals precipitated were extracted with chloroform. Then, the organic layer was dried over anhydrous sodium sulfate and the residue obtained by removing the solvent was applied to silica gel column chromatography to obtain 2.8 g of the title compound.
Reaction SMILES: C(O)C.C([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([O:27][CH3:28])[CH:19]=2)[CH2:14][C@H:13]1[F:29])C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH2:16][CH2:17][C@H:12]([NH2:11])[C@H:13]([F:29])[CH2:14]2)=[CH:19][C:20]=1[O:27][CH3:28]
Reactant: COc1cc(N2CC[C@H](NCc3ccccc3)[C@H](F)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N2CC[C@H](N)[C@H](F)C2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Ethanol (15 ml) and ethyl acetate (3.00 ml) were added to a flask charged with (3R,4S)—N-benzyl-3-fluoro-1-(3-methoxy-4-nitrophenyl)piperidin-4-amine (INTERMEDIATE 47) (1.4 g, 3.90 mmol) and Pd/C (0.415 g, 0.39 mmol). The flask was degassed and filled with H2. The reaction was stirred at RT for 2 h under hydrogen balloon. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure to give the title product (0.840 g, 90%).
Reaction SMILES: CO[C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:8][C:9](SC)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[CH3:30][O-:31].[Na+]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:6]2[CH:5]=[CH:4][C:3](=[O:29])[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:7]=2[N:8]=[C:9]([O:31][CH3:30])[N:10]=1
Reactant: COC(=O)/C=C/c1c(Nc2ccccc2Cl)nc(SC)nc1-c1ccccc1Cl
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1

Procedure:
Prepared as described above in Example 98 starting from (E)-3-[4-(2-chloro-phenylamino)-6-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid methyl ester and sodium methoxide to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.71 (s, 3H), 6.55 (d, 1H, J=9.6 Hz), 7.24-7.60 (m, 9H). LC MS (m/e)=398 (MH+). Rt=2.27 min
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[C:9]1([C@@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[C:9]1([C@@H:15]([NH:17][C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=2)[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[C@H](N)c1ccccc1
Solvent: C1CCOC1
Product: C[C@H](Nc1nccc(Cl)n1)c1ccccc1

Procedure:
To a stirred solution of 2,4-dichloropyrimidine (500 mg, 3.38 mmol, 1 eq) in THF (15 mL) was added (S)-1-phenylethylamine. After 48 h the precipitate was filtered off and washed with THF. The THF was removed under reduced pressure and the material was purified by silica gel chromatography (eluted with 4:1 hexanes/acetone) to give 167 mg of the desired product. [Note: 2-[(S)-1-phenylethylamino]-4-chloropyrimidine is the faster but minor regioisomer. The major, slower product is 2-chloro-4-[(S)-1-phenylethylamino]pyrimidine.]
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:8][CH:9]=2)[N:4]([Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:3]=1.[C:26]([Li])(C)([CH3:28])[CH3:27].C(I)CC>>[C:22]([Si:19]([CH3:21])([CH3:20])[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:6]=2)[C:2]([CH2:27][CH2:26][CH3:28])=[CH:3]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(Br)cn([Si](C)(C)C(C)(C)C)c2c1
Reactant: [Li]C(C)(C)C
Solvent: CCCI
Product: CCCc1cn([Si](C)(C)C(C)(C)C)c2cc(O[Si](C)(C)C(C)(C)C)ccc12

Procedure:
In analogy to the procedure described in example 21 b], 3-bromo-1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (example 21 a]) was treated with tert-butyllithium and propyl iodide to yield 1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-3-propyl-1H-indole as red liquid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][CH2:3][CH3:4].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.O>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1](=[NH:5])[CH2:2][CH2:3][CH3:4])=[CH:13][CH:12]=1
Reactant: CCCC#N
Reactant: Nc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(=N)Nc1ccc(Cl)cc1
Temperature: 115 °C
Reaction time: 5 h

Procedure:
To a solution of butyronitrile (compound 2, 7.5 mL, 86.2 mmol), AlCl3 in toluene was added 4-chloroaniline (compound 1, 10.0 g, 78.4 mmol). The reaction mixture was stirred at 115° C. for 5 hrs. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL) The aqueous layer was neutralized with saturated NaHCO3 (500 mL) and extracted with EtOAc (300 mL×2). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The obtained product (9.2 g, pale brown solid) was used for the next step without purification.
Reaction SMILES: Br[CH:2]([C@@H:8]([CH3:13])[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:14]([CH:2]([C@@H:8]([CH3:13])[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:15]=[N-:16]
Reactant: CCOC(=O)C(Br)[C@@H](C)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N=[N+]=[N-])[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
48.5 g of crude ethyl (3S)-2-bromo-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) were dissolved in 130 ml of DMF, and 17.98 g (276.55 mmol) of sodium azide were added at RT. The reaction mixture was stirred vigorously at RT overnight. The mixture was then diluted with 600 ml of ethyl acetate and washed with a 1:1 mixture, adjusted to pH 8, of sat. sodium chloride solution and water. After phase separation, the aqueous phase was re-extracted with 200 ml of ethyl acetate. The combined organic phases were washed successively twice with in each case 100 ml and twice with in each case 50 ml of a 1:1 mixture of sat. sodium chloride solution and water, dried over sodium sulphate and concentrated under reduced pressure without heating. The residue was briefly dried under high vacuum (careful when venting). This gave 32.8 g of ethyl (3R)-2-azido-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) as a crude product which was directly reacted further.