Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C[Si]([C:14]#[N:15])(C)C.C(N(CC)C(C)C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:15][CH2:14][CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1)[OH:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NCC(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled solution of 3-bromobenzaldehyde (1.58 mL) in THF (15 mL) were added trimethylsilyl cyanide (1.7 mL) and N,N-diisopropylethylamine (0.23 mL). The mixture was stirred at room temperature for 2d and at reflux for 2 h. The solution was allowed to cool to room temperature and then was slowly added to a cooled suspension of lithium aluminium hydride (769 mg) in THF (10 mL). The mixture was stirred at 0° C. for 10 min, the cooling bath was removed, and the mixture was heated at reflux for 3 h. After cooling to room temperature, ethylacetate was added slowly, followed by a mixture of Na2SO4/silicagel/H2O. After stirring the suspension for 30 min, the mixture was filtered, the filtrate was dried (Na2SO4), and concentrated in vacuo. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/ammonia 90:10:2) to give (1.59 g) 2-amino-1-(3-bromo-phenyl)-ethanol as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:17][C@@H:18]([C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:10](=O)[O:11]C(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(OC(=O)C)(=O)C>>[CH2:1]([O:8][N:9]([CH2:17][C@@H:18]([C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](CN(OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc(-c3ccccc3)cc2)CC1
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: CC(C)C[C@@H](CN(C=O)OCc1ccccc1)C(=O)N1CCN(c2ccc(-c3ccccc3)cc2)CC1
Yield: 52.2 %

Procedure:
The title product was obtained following the protocol of Example 1 (step c), but starting from tert-butyl (benzyloxy){(2S)-2-[(4-biphenyl-4-ylpiperazin-1-yl)carbonyl]-4-methyl pentyl}carbamate (219 mg, 0.46 mmol) and a preformed mixture of formic acid (875 μL; 23.2 mmol; 50 eq.) and acetic anhydride (220 μl; 2.32 mmol; 5.0 eq.) (mixture formed at 0° C. for 30 min). Purification by column chromatography (Silicagel, gradient from 33% EtOAc up to 50% EtOAc in c-Hex) gave the title product as a white solid (120 mg, 52%). HPLC, Rt: 4.60 min (purity: 99.7%). M+ (LC-MS (ESI)): 500.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][NH:5][C:4](=[S:7])[NH:3]1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[N:17]=[C:18]=[O:19]>CN(C)C=O>[CH3:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH3:9])[C:11]=1[NH:17][C:18]([N:5]1[CH2:6][C:2]([CH3:8])([CH3:1])[NH:3][C:4]1=[S:7])=[O:19]
Reactant: CC1(C)CNC(=S)N1
Reactant: Cc1cccc(C)c1N=C=O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)N1CC(C)(C)NC1=S
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.4 %

Procedure:
A mixture of 39.0 g (0.3 M) 4,4-dimethylimidazolidine-2-thione, 44.2 g (0.3 M) 2,6-dimethylphenyl isocyanate and 100 ml dimethylformamide was refluxed with stirring for 24 hours. After cooling to room temperature, the solution was filtered from a small amount of insoluble solid and poured into 300 ml water with efficient stirring. The precipitated product was filtered, washed well with water, and dried in vacuo. Yield 62.6 g, mp 228°-231° C. Recrystallization from 600 ml of boiling methanol yielded 46 g of N-(2,6-dimethylphenyl)-4,4-dimethyl-2-thioxo-1-imidazolidinecarboxamide as white crystalline product, mp 241.5°-243° C. A small sample was recrystallized from benzene to give an analytical sample, mp 245.5°-246° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[OH:10].[N+]([C:14]1[CH:15]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[C:17](=[CH:22][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19])([O-])=O.O>CN(C)C=O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[O:10][C:23]1[CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:16](=[CH:15][CH:14]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)OC
Reaction time: 5 h

Procedure:
2.4 g (0.012 mole) of sodium salt of 2,4-dichlorophenol and 2.4 g (0.010 mole) of dimethyl 4-nitrophthalate are dissolved in dry dimethylformamide and stirred at 130°-150° C. for 5 hours. After cooling, the mixture is poured into cold water, extracted with benzene, successively washed with dilute aqueous caustic soda, dilute hydrochloric acid and water, dried over sodium sulfate and then concentrated to obtain 2.5 g of an oily product. It was purified by column chromatography and there was obtained 1.6 g of the intended compound as a viscous oily product. Yield 45%.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(-c3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.1 %

Procedure:
In a flask were placed 2-amino-3-ethyl-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (20 mg, 0.06 mmol), copper acetate (3 mg, 0.01 mmol), phenylboronic acid (15 mg, 0.12 mmol), pyridine (11 μL, 0.12 mmol) and N,N-dimethylformamide (1 mL), followed by stirring at room temperature for 24 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[O:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH3:19][C:20]([CH3:22])=O.[BH3-]C#N.[Na+]>CC#N>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[O:4][CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([CH:20]([CH3:22])[CH3:19])[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCC2CCNCC2)c1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CC(C)N1CCC(COc2cc([N+](=O)[O-])ccc2Cl)CC1
Reaction time: 14 h

Procedure:
4-(2-Chloro-5-nitro-phenoxymethyl)-piperidine (7 g, 25.9 mmol) was dissolved in CH3CN (50 mL) and acetone (9.48 ml, 129 mmol) was added. NaBH3CN (2.6 g, 41.4 mmol) was added. After 14 h, the mixture was concentrated in vacuo and the residue was dissolved in EtOAc, washed with brine. The EtOAc portion was dried with Na2SO4, and evaporated. The title compound was purified by column chromatography using 0-75% of a 90:10:1 (CH2Cl2:MeOH: NH4OH) solution as the eluent to yield a yellow solid. MS(MH+)=NA; Calc'd 312.12 for C15H21ClN2O3.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@:22]([C:8]#[C:7][C:6]([O:10][CH2:11][CH3:12])=[O:9])([OH:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C#C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
n-Butyl lithium (2.28 ml, 1.6M solution in hexanes, 3.64 mmol) was added slowly to a cooled (-78° C.) solution of ethyl propiolate (0.370 ml, 3.64 mmol) in tetrahydrofuran (10 ml). the soluton was stirred for 10 min. at -78° C. after addition was complete then (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Description 1, 1,0 g, 3.64 mmol) in tetrahydrofuran (10 ml) was added, the temperature being maintained below -75° C. The mixture was stirred for a further 10 min, then warmed to -60° C. when glacial acetic acid (1 ml) was added. The mixture was warmed to room temperature and poured into saturated aqueous sodium hydrogen carbonate (20 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10), to give the title compound as a gum (801 mg, 59%), 1H NMR (250 MHz, CDCl3) δ7.50 (2H, m), 7.35 (3H, m), 5.49 (1H, s), 4.25 (2H, q, J 7.12 Hz), 4.15 (1H, m), 3.02 (1H, m), 2.23 (2H, m), 2.00 (2H, m), 1.78 (1H, m), 1.37 (9H, s), and 1.29 (3H, t, J 7.12 Hz), m/z (ES+) 374 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH3:26].O>CN(C)C=O>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH2:24][CH2:25][CH3:26])[C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 10.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide in 500 ml of dry dimethylformamide under argon, was added 2.0 g of sodium hydride (50% in oil). This mixture was stirred for 1 hour, then 3.75 ml of 3-bromopropane was added. This mixture was stirred for 2.5 days, then poured into 1 liter of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed as described in Example 1, giving 3.60 g of the desired product as yellow crystals, mp 145°-149° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([Si](C)(C)C)([F:19])[F:18]>CN(C)C=O>[CH2:1]([N:3]1[C:7]([CH:8]([OH:9])[C:17]([F:19])([F:18])[F:16])=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cncc1C=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cncc1C(O)C(F)(F)F
Yield: 47.1 %

Procedure:
According to Reference Example 8-2, by use of 1-ethyl-1H-imidazole-5-carbaldehyde (115 mg, 0.926 mmol) dissolved in N,N-dimethylformamide (2.3 mL), potassium carbonate (26 mg, 0.19 mmol) and (trifluoromethyl)trimethylsilane (0.300 mL, 2.04 mmol), the mixture was stirred and reacted at a temperature of room temperature to 50° C. for 6.8 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=10/1) was performed to give 1-(1-ethyl-1H-imidazol-5-yl)-2,2,2-trifluoroethanol (Compound DU) (84.7 mg, yield: 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44].[Cl-].[NH4+]>C(Cl)Cl>[CH3:42][S:43]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:23])(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 23 h
Yield: 79.7 %

Procedure:
6.62 gram (14.1 mmol) of (−)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-1a-1)) was dissolved in 282 ml of methylene chloride, followed by the addition of 4.7 ml (57.8 mmol) of pyridine and 4.1 ml (53.6 mmol) of methanesulfonyl chloride at 0° C. The reaction solution was stirred at room temperature for 23 hours. To the reaction solution, 200 ml of saturated aqueous solution of ammonium chloride was added and extracted with 200 ml of methylene chloride. The extract was washed with 200 ml of brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 2:3 mixture of ethyl acetate and hexane) to obtain 6.15 gram of the titled compound.
Reaction SMILES: Br[CH:2]1[CH:10]2[C:5](=[CH:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9]2=[O:11])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:3]1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5]2[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)[N:15]=3)[CH:3]=[C:2]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[C:10]=2[C:9](=[O:11])[CH2:8]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC1(C)C=C2C(C(=O)C1)C(Br)CN2c1cccc(Cl)n1
Product: CC1(C)CC(=O)c2c(-c3nccs3)cn(-c3cccc(-c4nccs4)n3)c2C1
Yield: 13 %

Procedure:
In the same way as described in Example 15, Step 4 using 3-bromo-1-(6-chloropyridin-2-yl)-6,6-dimethyl-1,2,3,4-tetrahydroindol-4-one and 2-tributylstannylthiazole, the title compound (35 mg; 13%) was isolated as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.21 (6H,s), 2.55 (2H,s), 3.24 (2H,s) 7.35 (1H,d, J=3.1 Hz), 7.50-7.53 (2H,m), 7.81 (1H,d, J=3.1 Hz), 7.97-8.02 (3H,m), 8.20 (1H,d, J=7.8 Hz). MS (ES+) 407 (M+1).
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[NH:14])[NH2:13])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])(=O)=O.CS(O)(=O)=O.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[NH:14])[NH2:13])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])(=[O:25])[CH3:24]
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Product: CC(=O)Oc1ccc(C(=N)N)cc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
To a suspension of 3.0 g of 4-amidino-2-nitrophenol methanesulfonate in 15 ml of acetic anhydride, was added 0.5 ml of methanesulfonic acid. The mixture was refluxed with stirring for 10 to 20 minutes. The crystals dissolved slowly, forming a clear yellow solution. Upon standing at room temperature, colorless crystals separated out of the solution. The crystals were ashed with ethyl ether and recrystallized from ethanol to obtain 3.0 g of colorless needle crystals of 4-amidino-2-nitrophenyl acetate methanesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5](CCl)[CH2:6][C:7]1[N:16]=[C:15](O)[C:14]2[C:9](=[CH:10][C:11]([C:18]3[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:12][CH:13]=2)[N:8]=1)[CH3:2].O=P(Cl)(Cl)[Cl:33].N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[N:16]=[C:15]([Cl:33])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[C:23]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:12][CH:13]=2)[N:8]=1)[CH3:2]
Reactant: CCOC(=O)C(CCl)Cc1nc(O)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)cc2n1

Procedure:
Reflux a mixture of 2-chloromethyl-3-[4-hydroxy-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propionic acid ethyl ester (600 mg, 1.6 mmol), POCl3 (445 μl, 4.77 mmol), and 2,6-lutidine (596 μl, 4.77 mmol) in CHCl3 (20 ml) for 60 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (Na2SO4) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 3-[4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propionic acid ethyl ester.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH:24]([CH3:27])[CH2:25][OH:26]>>[CH2:18]([C:13]1[C:12]([CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH:24]([CH3:27])[CH2:25][OH:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(N)CO
Reactant: CCCCc1noc(C)c1CNc1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1CNc1ccc(C(=O)NC(C)CO)cn1
Temperature: 50 °C
Yield: 52.9 %

Procedure:
A mixture of 6-[(3-butyl-5-methyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid methyl ester (90 mg, 0.3 mmol), rac-2-amino-1-propanol (27 mg, 0.36 mmol) and TBD (12 mg, 0.09 mmol) was heated at 50° C. for 4 h under argon. The reaction mixture was concentrated onto silica then purified by chromatography (silica, 0 to 7% methanol in ethyl acetate) to give the title compound (55 mg, 54%) as a colourless oil. MS: m/e=347.3 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[F:14][C:15]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>>[F:14][C:15]1[CH:22]=[C:21]([O:23][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1ccc(O)cc1F
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Product: N#Cc1ccc(Oc2ccc(C=O)cc2C(F)(F)F)cc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluoro-3-(trifluoromethyl)benzaldehyde and 2-fluoro-4-hydroxybenzonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:31]([Br:32])=[CH:30][C:5]([CH2:6][C@H:7]([C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[Br:33].[BH4-].[Na+].C(O)(=O)C>O1CCOCC1>[NH2:1][C:2]1[C:31]([Br:32])=[CH:30][C:5]([CH2:6][C@@H:7]([NH:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:16][N:18]2[CH2:19][CH2:20][CH:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[CH2:22][CH2:23]2)=[CH:4][C:3]=1[Br:33]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(Br)c(N)c(Br)c1)C(=O)N1CCC(N2CCCCC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(Br)c(N)c(Br)c1)CN1CCC(N2CCCCC2)CC1
Temperature: 5 °C

Procedure:
To a solution of 10 g (0.017 mol) of 1-[4-amino-3,5-dibromo-N-[(1,1-dimethylethoxy)carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine in 350 ml of dioxane were added 3.1 g (0.082 mol) of sodium borohydride and the reaction mixture was cooled to 5° C. Then a solution of 4.92 g (0.082 mol) of acetic acid in 100 ml of dioxane was added dropwise with stirring. The reaction mixture was stirred for a further hour at room temperature and for 3 hours at 85° C. Then ice water was added, the organic solvent was removed in vacuo and the aqueous residue was repeatedly extracted with methylene chloride. The combined organic phases were dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylene chloride/methanol/cyclohexane/conc. aqueous ammonia=3600/150/150/20 (v/v/v/v). 4.1 g (42% of theory) of a colourless foam were obtained.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:1]1[C:6]2[CH2:7][N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCCI
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCCCCN1Cc2ccccc2Oc2ccccc21
Temperature: 70 °C
Reaction time: 60 h
Yield: 36.9 %

Procedure:
Title compound 398 (0.304 g, 1.54 mmol) was dissolved in acetonitrile (5.0 mL) and the ethyl 7-iodoheptanoate (0.613 g, 2.16 mmol) and the potassium carbonate (0.639 g, 4.62 mmol) were added. The reaction mixture was stirred at 70° C. for 60 hours. The mixture was cooled down and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography with 10% ethyl acetate in hexanes to afford title compound 399 (201 mg, 37%). MS (m/z): 354.2 (M+H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])=[C:8]([CH3:17])[C:7]=1[CH3:18].S(O)(O)(=O)=O.[NH2:26][OH:27].S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:18][C:7]1[C:8]([CH3:17])=[C:9]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH:3]=[N:26][OH:27]
Reactant: NO
Reactant: CCOCCc1ccc(OCC(OC)OC)c(C)c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOCCc1ccc(OCC=NO)c(C)c1C
Temperature: 70 °C
Reaction time: 10 h
Yield: 93 %

Procedure:
A mixture of 2.1 liters of methanolic solution of 760 g of 1-(2,2-dimethoxyethoxy)-4-(2-ethoxyethyl)-2,3-dimethylbenzene and 2 1 liters of aqueous solution of 466 g of hydroxylamine sulfate was heated to 70° C. To the mixture added was 12 N sulfuric acid until the pH became 0.5, and the mixture was stirred vigorously. Since the pH is lowers with the progress of the reaction, an aqueous 12 N sodium hydroxide solution was added dropwise so as to maintain pH at 0.5. The reaction was monitored by HPLC, and when the conversion exceeded 95%, the reaction mixture was cooled to around room temperature. Generally, the reaction requires about 10 hours. After pH was adjusted to 6.5 with 12 N-NaOH, the solid formed was filtered The filtered product was washed with 1.0 liter of warm water, and dried under reduced pressure to obtain the title product. m.p. 102°-105° C., amount obtained 676 g, purity 93%, yield 93%.
Reaction SMILES: C1([C@@H]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]3)[CH2:10]2)C)C=CC=CC=1.CC(O)=O.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[C@@H:16]12[NH:9][CH2:10][C@@H:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2
Reactant: [H][H]
Reactant: C[C@@H](c1ccccc1)N1C[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H]2CN[C@H]2C1
Yield: 75 %

Procedure:
To a solution of (1R,6S)-tert-butyl 8-((S)-1-phenylethyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.5 g, 75%) in EtOH (50 mL) was added AcOH (1.5 mL). The resulting mixture was cycled through an H-Cube containing a 20% Pd(OH)2/C catalyst cartridge at 50° C. and 100 bar of hydrogen pressure. After 16 hours the resulting mixture was removed from the H-Cube and poured over a saturated sodium carbonate solution (100 mL). The aqueous layer was extracted with DCM (50 mL) four times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (755 mg, 75%) which was used in the next step without purification. MS (ESI) mass calcd. for C11H20N2O2, 212.2; m/z found, 213.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 4.21-4.02 (m, 1H), 3.84-3.59 (m, 3H), 3.47-3.36 (m, 1H), 3.33 (dd, J=8.3, 4.4 Hz, 1H), 3.28-3.20 (m, 1H), 2.91-2.71 (m, 2H), 1.94-1.81 (m, 1H), 1.81-1.68 (m, 1H), 1.46 (s, 9H).