Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:29]1([CH2:28][O:27][C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:32])=[C:11]([C:9]([NH:8][CH:5]4[CH2:4][CH2:3][N:2]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:7][CH2:6]4)=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:30][CH2:31]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]([OH:24])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CC(C)=O>[CH3:1][N:2]([O:24][CH2:32][C:33]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:38])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: CN(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(OCC(=O)C(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of N-methyl-N[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]hydroxyamine (700 mg., 1.93 mm) K2CO3 (320 mg.), 1-bromo-3,3-dimethylbutan-2-one (520 mg.) and acetone (10 ml.) is refluxed for about 16 hours. Then, the mixture is filtered and filtrate concentrated. The concentrate is purified by prep. TLC using 20% ethyl acetate/hexane to give N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]t-butylcarbonylmethoxyamine (IVA; R3 is H, n is one, and R4 is t-butyl).
Reaction SMILES: Br[C:2]1N=C(SC)C(=O)N(C(CC)CC)[CH:7]=1.Br[C:17]1[N:18]=[C:19]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([Cl:39])=[CH:35][C:36]=3[Cl:38])[CH2:31][CH2:30]2)[C:20](=[O:28])[N:21]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:22]=1.C([Al](CC)CC)C>>[Cl:39][C:34]1[CH:33]=[C:32]2[C:37](=[C:36]([Cl:38])[CH:35]=1)[N:29]([C:19]1[C:20](=[O:28])[N:21]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:22]=[C:17]([CH2:2][CH3:7])[N:18]=1)[CH2:30][CH2:31]2
Reactant: CCC(CC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O
Reactant: CCC(CC)n1cc(Br)nc(SC)c1=O
Agent: CC[Al](CC)CC
Product: CCc1cn(C(CC)CC)c(=O)c(N2CCc3cc(Cl)cc(Cl)c32)n1

Procedure:
Prepared in a similar fashion as described for XXXII (Example 481, part B) using 5-bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone (Example 507) as the starting material and triethylaluminum in place of trimethylaluminum. mp 136-137° C.; 1H NMR (300 MHz, CDCl3): δ 7.14 (d, J=1.8 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.54 (s, 1 H), 4.90-4.79 (m, 1 H), 4.30 (t, J=8.1 Hz, 2 H), 3.14 (t, J=8.1 Hz, 2 H), 2.44 (q, J=7.4 Hz, 2 H), 1.84-1.69 (m, 2 H), 1.67-1.61 (m, 2 H), 1.18 (t, J=7.5 Hz, 3 H), 0.86 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C19H24N3OCl2 (M+H)+: 380.1296; Found m/z 380.1280.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][OH:8])[NH:4][N:3]=1.[C:9]([C:15](OC)=[O:16])#[C:10][C:11]([O:13][CH3:14])=[O:12]>CO>[OH:16][C:15]1[N:3]2[N:4]=[C:5]([CH2:7][OH:8])[N:6]=[C:2]2[N:1]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=1
Reactant: Nc1n[nH]c(CO)n1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)c1cc(O)n2nc(CO)nc2n1
Temperature: 30 °C
Reaction time: 20 h

Procedure:
In 1.7 liters of methanol was suspended 60 g of 3-amino-5-hydroxymethyl-1,2,4-triazole and 75 ml of dimethyl acetylenedicarboxylate was added to the suspension, and the mixture was stirred at 30 ° C. for 20 hours. Precipitates were collected by filtration, washed with methanol and then dried to obtain 25.7 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Br)=[C:6]([Br:10])[CH:5]=[CH:4][CH:3]=1.[C-:11]#[N:12].[K+]>C(O)C.O>[Br:10][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:11]#[N:12]
Reactant: Clc1cccc(Br)c1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1c(Cl)cccc1Br
Yield: 52.3 %

Procedure:
A solution of 31.3 g of the crude 6-chloro-alpha,2-dibromotoluene in 100 ml of warm ethanol is treated with a solution of 6.7 g of potassium cyanide in 10 ml of water and the mixture is heated at reflux for 4 hours. The crude product is isolated by pouring the cooled reaction mixture into water and filtering the resulting precipitate. Recrystallization of this solid from aqueous ethanol then gives 12.4 g of 2-bromo-6-chlorophenylacetonitrile, mp 82°-84° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[C:1]1([C:7]2[N:11]=[C:10]([C:12]3([CH2:18][NH:19][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[N:23]=[C:22]([C:21]([F:37])([F:36])[F:20])[O:26][N:25]=5)[CH:28]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1(c2nc(-c3ccccc3)n[nH]2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2nc(-c3ccccc3)n[nH]2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 24 %

Procedure:
This compound was synthesized from (4-(3-phenyl-1H-1,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (80 mg, yield 24%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H), 8.02 (dd, J=7.3 Hz, 1.8 Hz, 2H), 7.89 (br s, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.46 (m, 3H), 3.97-3.92 (dt, J=11.9 Hz, 4.5 Hz, 2H), 3.83 (d, J=5.8 Hz, 2H), 3.71-3.66 (m, 2H), 2.44-2.42 (d, J=13.6 Hz, 2H), 1.96-1.89 (ddd, J=13.4 Hz, 9.2 Hz, 3.5 Hz, 2H). MS (ESI) m/z: Calculated for C24H21F3N6O3: 498.16. found: 499.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[NH:13][N:14]=[C:15]3[C:20]=2[CH:19]=[CH:18][C:17]([F:21])=[CH:16]3)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O>[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=[C:15]3[C:20]=2[CH:19]=[CH:18][C:17]([F:21])=[CH:16]3)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: ClCc1ccccc1
Reactant: CC(=O)N1CCC(c2[nH]nc3cc(F)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2c3ccc(F)cc3nn2Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a stirred mixture of 15.8 parts of a sodium hydride dispersion 50% and 660 parts of dimethyl sulfoxide were added portionwise 78.4 parts of 1-acetyl-4-(6-fluoro-2H-indazol-3-yl)piperidine under nitrogen atmosphere. Upon complete addition, stirring was continued for 1 hour at room temperature. 42 Parts of chloromethylbenzene were added dropwise during 45 minutes. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured into crushed ice and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of methylbenzene and methanol (90:10 by volume) as eluent. The first fraction was collected and the eluent was evaporated, yielding 91 parts (86.3%) of 1-acetyl-4-[6-fluoro-2-(phenylmethyl)-2H-indazol-3-yl]piperidine as a residue (int. 1).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[N:26]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[N:26]=[C:22]([CH3:21])[S:23][CH:24]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.37 min.; [M+H]+: 437.10 g/mol.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:14](=[C:15]4[C:20]=2[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li:25])CCC>>[Li:25][CH:10]1[C:9]2[C:14](=[C:15]3[C:20](=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=2)[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:13][CH2:12][CH2:11]1
Reactant: c1ccc(-c2nc3c(c4c2CCCC4)CCCC3)cc1
Reactant: [Li]CCCC
Product: [Li]C1CCCc2c1nc(-c1ccccc1)c1c2CCCC1

Procedure:
By the method of Example 2, 1,2,3,4,7,8,9,10-octahydro-6-phenyl-phenanthridine is reacted with n-butyl-lithium solution to give 1,2,3,4,7,8,9,10-octahydro-4-lithio-6-phenylphenanthridine which in turn is reacted with trimethylsilyl isothiocyanate to give 1,2,3,4,7,8,9,10-octahydro-6-phenylphenanthridine-4-thiocarboxamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].[N:14]1([CH2:20][C:21]2[O:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[BH4-].[Na+]>C(O)C>[N:14]1([CH2:20][C:21]2[O:27][C:24]([CH2:25][NH:1][CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[NH:6][C:5]3=[O:13])=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1ccc(CN2CCCCC2)o1
Reactant: NCCn1c(=O)[nH]c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1CCNCc1ccc(CN2CCCCC2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.4 %

Procedure:
In 100 ml of dry ethanol were dissolved 1.2 g (6.78 mmol) of Compound j and 1.3 g (6.78 mmol) of 5-piperidinomethylfurfural and the solution was stirred at room temperature for 20 hours. The reaction mixture was then cooled with ice and 1.18 g (31.1 mmol) of sodium borohydride was gradually added. The mixture was further stirred under ice-cooling for 1.5 hours. The reaction mixture was then concentrated, and after addition of methylene chloride, the resulting solution was washed with 2 portions of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. Finally the residue was purified by silica gel column chromatography (chloroform-methanol=10:1→chloroform-methanol-triethylamine=100:10:1) to give 1.26 g (52.9%) of Compound 18 as light yellow oil.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][S:19][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]([OH:28])=[C:8]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][S:19][C:9]=23)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)c2snc(-c3ccccc3)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2ccc(F)cc2)c2snc(-c3ccccc3)c2c1O
Yield: 67.5 %

Procedure:
A mixture of 7-(4-fluoro-phenyl)-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (69 mg, 0.175 mmol), glycine (394 mg, 5.25 mmol), and NaOMe (8.75 mL, 4.37 mmol, 0.5 M solution in MeOH) was refluxed for 24 h. After the mixture was cooled to r. t. it was concentrated in vacuo. The residue was dissolved in water (25 mL) and washed with CH2Cl2 (2×15 mL). The aqueous solution was then acidified by addition of aqueous 1N HCl solution. The resulting precipitate was sucked off, washed with water, and dried in vacuo to give the title compound as white solid (50 mg): MS (m/z) 424.2 (M+1).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)=[O:57])[CH3:54])=[O:51])[N:5]=1.C1(C)C=CC=CC=1.CO>C(O)=O>[CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:27]=[N:28][NH:29][N:30]=3)=[CH:16][CH:15]=2)[C:11]2[C:10]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1

Procedure:
A solution of trityl candesartan cilexetil (TCC, 30.0 g, 35.17 mmol), toluene (180 mL), methanol (180 mL) and formic acid (1.6 g) was refluxed for about 10 h (HPLC control), the solvents were evaporated at 60° C./30 mbar to give a residue as a viscous oil.
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[C:9](OCC3OC3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=O)C.[CH2:19](O)C>Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C=CC=C2C=1CCCN2C(=O)C>[NH2:4][CH:5]1[CH2:6][CH2:7][C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:19]1
Reactant: CCO
Reactant: CC(=O)N1CCCc2c(OCC3CO3)cccc21
Agent: CC(=O)N1CCCc2c(OCC(O)CNC3CCc4ccccc4C3)cccc21
Agent: Cl
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 1-acetyl-5-(2,3-epoxypropoxy)-1,2,3,4-tetrahydroquinoline (2.77 g) and 2-aminotetralin (1.49 g) in ethanol (30 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-acetyl-1,2,3,4-tetrahydroquinolin-5-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 66, wherein Z is methyl, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:40][C:41]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:42]=1[CH:43]=O.C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[CH3:7][O:6][C:4](=[O:5])[C:3]([C:2](=[O:1])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:43][C:42]1[C:41]([Cl:40])=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:49]
Reactant: COC(=O)CC(=O)CCc1ccccc1COCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1c(Cl)cccc1Cl)C(=O)CCc1ccccc1COCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h

Procedure:
A mixture of methyl 3-oxo-5-[2-[[2-(tritylamino)ethoxy]methyl]phenyl]pentanoate (3.33 g, 6.38 mmol), 2,6-dichlorobenzaldehyde (1.12 g, 6.38 mmol), acetic acid (0.5 ml), piperidine (0.5 ml) and benzene (50 ml) was stirred for 4 hours at reflux temperature azeotropically. The reaction mixture was quenched with water (40 ml) and the whole was extracted with Et2O (20 ml×2). The combined extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to afford the titled compound as a yellow oil. (quant.)
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=O)[C:6]([OH:8])=[O:7].[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[CH3:13].C([BH3-])#N.[Na+]>O>[C:6]([CH:5]([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[CH3:13])[CH2:4][CH:3]([CH3:10])[CH3:2])([OH:8])=[O:7]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CC(C)CC(N[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
A solution of the sodium salt of 4-methyl-2-oxopentanoic acid (414 mg) and L-alanyl-L-tryptophan (150 mg) in water are adjusted to pH 7 with caustic and treated with sodium cyanoborohydride (103 mg) at room temperature for several days. The product is adsorbed on strong acid ion exchange resin and eluted with 2% pyridine in water. The product rich cuts are freeze dried affording 189 mg of fluffly white solid. The mass spectrum shows a molecular ion at 389 m/e and peaks at 187 m/e and 158 m/e for the fragments shown respectively: ##STR16## The nmr spectrum in D2O is consistent with structure.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:30])([F:29])[C:10]([N:12]1[CH2:28][CH2:27][C:15]2([CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH2:14][CH2:13]1)=[O:11]>>[F:30][C:9]([F:8])([F:29])[C:10]([N:12]1[CH2:28][CH2:27][C:15]2([CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(C(=O)C(F)(F)F)CC2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCC2(CCNC2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
TFA (1 ml) was added to a stirred solution of tert-butyl 8-(2,2,2-trifluoroacetyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (840 mg, 2.5 mmol) in MC (4 ml) and the mixture was stirred at RT for 12 h. The reaction mixture was then concentrated under reduced pressure and azeotroped with MC (2×10 ml). The crude product was dried and used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:16]([OH:18])=O)[C:11](=[O:26])[CH:10]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:16]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)=[O:18])[C:11](=[O:26])[CH:10]=1
Reactant: O=C(O)C(Cc1cccnc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(NC(=O)C(Cc2cccnc2)n2ccc(-c3cc(Cl)ccc3Br)cc2=O)cc1

Procedure:
244 mg (purity 57%, 0.32 mmol) of 2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoic acid (racemate) and 1.2 eq. of methyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 65 mg (purity 85%, 30% of theory)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:12][C:13]([F:20])([F:19])[C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([N:16]2[CH:17]=[CH:18][C:14]([C:13]([F:20])([F:19])[F:12])=[N:15]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccn(-c2ncccc2C(F)(F)F)n1
Temperature: 100 °C
Yield: 62.2 %

Procedure:
A mixture of 2-chloro-3-trifluoromethylpyridine (3.62 g, 21 mmol), 3-trifluoromethylpyrazole (2.7 g, 20 mmol), and potassium carbonate (6.0 g, 43 mmol) were heated at 100° C. for 18 h. The cooled reaction mixture was added to ice/water (100 mL). The mixture was extracted twice with ether (100 mL) and the combined ether extracts were washed twice with water (100 mL). The organic layer was dried with magnesium sulfate and concentrated to an oil. Chromatography on silica gel with hexanes:ethyl acetate (8:1 to 4:1) as eluent gave the title compound (3.5 g) as an oil.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:22]([O:23]C(=O)C)[C@H:21]([O:27]C(=O)C)[CH2:20][S:19][C@H:9]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)(=O)C>CO>[O:10]([C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=1)[C@@H:9]1[S:19][CH2:20][C@@H:21]([OH:27])[C@H:22]([OH:23])[C@H:8]1[OH:7]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 129.5 %

Procedure:
1.5 ml of a solution of sodium methylate in methanol (8% w/v of Na) are added under an inert atmosphere to a suspension of 10 g (25.4.10-3 mol) of 4-cyanophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside in 200 ml of methanol. The reaction mixture is stirred at room temperature for 30 min, neutralized by the addition of Amberlite® IR 120 H+ resin and filtered. After evaporation to dryness, the residue is crystallized from methanol to give 8.8 g (yield: 73%) of the expected product.
Reaction SMILES: [N:1]12[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:10]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]2.[C:27](Cl)(=[O:30])[O:28][CH3:29]>>[C:27]([N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:28][CH3:29])=[O:30])[CH2:20][CH2:19][N:10]2[CH2:11][CH2:12][N:13]([C:27]([O:28][CH3:29])=[O:30])[CH2:14][CH2:15][N:16]([C:27]([O:28][CH3:29])=[O:30])[CH2:17][CH2:18][N:1]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]2)[CH2:26][CH2:25]1)([O:28][CH3:29])=[O:30]
Reactant: COC(=O)Cl
Reactant: C1CNCCN2CCNCCNCCN(CCN1)CCOCCOCC2
Product: COC(=O)N1CCN2CCOCCOCCN(CCN(C(=O)OC)CC1)CCN(C(=O)OC)CCN(C(=O)OC)CC2

Procedure:
In a manner similar to that described in Example 7, treat 4,7-dioxa-1,10,13,16,21,24-hexaazabicyclo[8,8,8]hexacosane (compound of Example 70C) with methyl chlorocarbonate to obtain 13,16,21,24-tetracarbomethoxy-4,7-dioxa-1,10,13,16,21,24-hexaazabicyclo[8,8,8]hexacosane as a viscous liquid.
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7]([CH2:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:21])=[O:8])C>C(O)C>[C:7]([CH2:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:21])([OH:8])=[O:6]
Reactant: CCOC(=O)CN1C(=O)COc2cc(F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1C(=O)COc2cc(F)ccc21
Yield: 97.3 %

Procedure:
Sodium hydroxide (0.7 g) and water (10 ml) were added to a mixture of 4-ethoxycarbonylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (3.7 g) and ethanol (20 ml), and the mixture was refluxed under heating for 5 hours. After the reaction, the solvent was concentrated, and dissolved in water (50 ml), and washed with methylisobutyl ketone, the aqueous layer was acidified with hydrochloric acid, and extracted with methyl isobutyl ketone, then dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was mixed with a mixed solvent of toluene-hexane (1:5), the mixture was filtered off to give the desired 4-carboxymethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (3.2 g). mp. 183°-184° C.
Reaction SMILES: [S:1]1[C:5]([C:6]2([OH:16])[CH2:15][CH2:14][C:9]3(OCC[O:10]3)[CH2:8][CH2:7]2)=[CH:4][N:3]=[CH:2]1.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[OH:16][C:6]1([C:5]2[S:1][CH:2]=[N:3][CH:4]=2)[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1
Reactant: OC1(c2cncs2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CCC(O)(c2cncs2)CC1

Procedure:
8-Thiazol-5-yl-1,4-dioxa-spiro[4.5]decan-8-ol (4.35 g, 18.0 mmol) as prepared in the previous step was treated with 1N HCl (˜10 mL) in acetone (20 mL) at room temperature for 4 hours. The reaction was neutralized with saturated NaHCO3 solution and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a pale yellow solid.