Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[C:12]3=[N:13][C:14]([NH2:16])=[N:15][N:11]3[CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[S:20][N:19]=1>>[CH3:17][C:18]1[N:22]=[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([NH:16][C:14]3[N:13]=[C:12]4[CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[O:8][CH2:9][CH2:10][N:11]4[N:15]=3)[CH2:27][CH2:28]2)[S:20][N:19]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1nc2n(n1)CCOC2c1ccccc1
Product: Cc1nsc(N2CCC(Nc3nc4n(n3)CCOC4c3ccccc3)CC2)n1

Procedure:
Prepared in analogy to example 261a employing 8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-amine and 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one (see example 1d). The title compound was obtained as an white foam.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH2:23])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].C([NH:33][CH2:34][C:35](O)=[O:36])(OC(C)(C)C)=O.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH:23][C:35](=[O:36])[CH2:34][NH2:33])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCN(CC)c1ccc(NC(=O)C2(N)CCc3ccccc3C2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)C2(NC(=O)CN)CCc3ccccc3C2)cc1
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a mixture of 2-amino-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (4-diethylamino-phenyl)-amide (100 mg, 0.3 mmol) from Example 8 and N-Boc-glycine (52 mg, 0.3 mmol) in DMF (1.0 mL) was added Et3N (61 mg, 0.6 mmol) and TBTU (96 mg, 0.3 mmol). The mixture was stirred overnight and the precipitates were collected by filtration(130 mg) and dissolved in dichloromethane (10 mL) and TFA (5.0 mL). The mixture was concentrated under reduced pressure and ethyl acetate (20 mL) were added and the resulting solution was washed with 1N NaOH. The organic phase was dried over MgSO4 and then concentrated under reduced pressure to give 2-(2-amino-acetylamino)-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (4-diethylamino-phenyl)-amide (70 mg).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH:18]([CH3:20])[CH3:19])[C:3]=1[O:22][CH2:23][CH3:24].[CH3:25][CH2:26][O:27][C:28]([CH:30](P(OCC)(OCC)=O)[F:31])=[O:29].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH:18]([CH3:19])[CH3:20])=[C:30](/[F:31])\[C:28]([O:27][CH2:26][CH3:25])=[O:29])[C:3]=1[O:22][CH2:23][CH3:24]
Reactant: CCOc1c(C(=O)C(C)C)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(\c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)C)C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-methyl-propan-1-one (Compound A-111, 234 mg, 0.60 mmol) and triethyl 2-fluoro-2-phosphonoacetate (576 mg, 2.38 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 1.48 mL, 2.38 mmol) in THF to produce the title compound as a clear oil after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[NH:18][NH2:19].[OH-].[Na+]>ClCCl>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:10]=[C:9]([Cl:17])[C:8]=1[NH:18][NH:19][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 8.5 h
Yield: 91 %

Procedure:
A solution of chloroacetyl chloride (2.3 ml, 1.08 equivalents) in anhydrous dichloromethane (30 ml) was added during 30 minutes to a stirred solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (6.1 g, 24.89 mmol) in anhydrous dichloromethane (60 ml) maintaining between 5 and 12° C. under an argon atmosphere. The mixture was then stirred for 5-12 hours at 20° C. A solution of sodium hydroxide (11.2 ml of 10%) and dichloromethane were added and the organic phase washed (water), dried (magnesium sulfate) and evaporated to give the title compound (7.25 g) as a white solid, NMR 4.05 (s, 2H), 6.77 (s, 1H), 7.47 (s, 2H), 8.6 (s, 1H). The yield was 91%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:21]1[CH2:31][CH2:30][C:24]2[N:25]=[CH:26][N:27]=[C:28](Cl)[C:23]=2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:28]2[C:23]3[CH2:22][N:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:31][CH2:30][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 92.6 %

Procedure:
To a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (6.21 g, 33.16 mmol) and 6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (9 g, 34.65 mmol) in 2-Me-THF (100 mL) was added under nitrogen tBuOK (8.17 g, 72.95 mmol). The mixture was stirred at rt for 25 min. The mixture was quenched with H2O. The organic layer was washed with brine. The resulting organic solution was concentrated in vacuo to provide (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (12.6 g, 89% yield) as a yellow gum.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:17]>>[NH2:17][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCCOCn1cc(Cl)c2c(Cl)ncnc21
Reactant: N
Product: Nc1ncnc2c1c(Cl)cn2COCCO
Temperature: 135 °C
Reaction time: 10 h

Procedure:
4,5-Dichloro-7-(2-hydroxyethoxymethyl)pyrrolo[2,3-d] pyrimidine (7b, 0.07 g) was covered with methanolic-ammonia (20 mL) and heated in a sealed reaction vessel at 135 degrees C. for 10 hours. The solvent was evaporated in vacuo to give a thick syrup. This syrup was subjected to column chromatography and elution of the silica gel column (20×3 cm) with 5% MeOH in CHCl3 furnished colorless needles of 10, after evaporation of the appropriate UV absorbing fractions; 0.04 g. (66.6%), mp 149-150 degrees C. 1H-NMR (DMSO-d6): δ 8.14 (s, 1, C2-H), 7.56 (s, 1, C6-H), 6.92 (bs, 2, exchangeable with D2O, NH2), 5.49 (s, 1, N7-CH2), 4.64 (bs, 1, exchangeable with D2O, OH), 3.43 (m, 4, CH2): UVλmax nm (ε× 104) (pH 7) 214 (2.5), 278 (1.3); (pH 1) 233 (2.8), 280 (1.3); (pH 11) 227 (1.4), 278 (1.3).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>C(#N)C>[F:1][C:2]1[C:3]([N:26]2[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH3:21])[CH2:25]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CNCC1CCNC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CC#N
Product: CNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OCC4C)C1
Yield: 226.4 %

Procedure:
0.75 g (2.7 mmole) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 40 ml acetonitrile, and 0.91 g (0.80 mmole) of N-methyl-3-pyrrolidinemethanamine were refluxed overnight. The solvent was removed at reduced pressure and the residue tititrated with 40 ml of methanol. The precipitate was filtered, washed repeatedly with 95% ethanol and finally with ether until dry to give 0.68 g of 9-fluoro-2,3-dihydro-3-methyl-10-[3-[(methylamino)methyl]-1-pyrrolidinyl]-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, mp 235°-237.5° C.
Reaction SMILES: [CH:1](O)=O.[C:4]([N:12]1[CH2:17][CH:16]2[CH2:18][CH2:19][CH:13]1[CH2:14][NH:15]2)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C=O>>[C:4]([N:12]1[CH2:17][CH:16]2[CH2:18][CH2:19][CH:13]1[CH2:14][N:15]2[CH3:1])(=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=CO
Reactant: O=C(c1ccccc1)N1CC2CCC1CN2
Agent: C=O
Product: CN1CC2CCC1CN2C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 91 h
Yield: 100.3 %

Procedure:
To 7.4 ml of 88% formic acid (0.17 mole) was added 14.6 g (0.0675 mole) of 2-benzoyl-2,5-diazabicyclo[2.2.2]octane with stirring at 0° C. A 36% aqueous solution of formaldehyde (6.0 ml, 0.078 mole) was added, and, after visible gas evolution had ceased, the mixture was heated at 80° C until renewed gas evolution has stopped 91 hour). After 3 hours at 90°-100° C, volatiles were removed in vacuo. The residue was dissolved in water, made alkaline with 20% aqueous sodium hydroxide, and extracted with chloroform. After drying with sodium sulfate, the extracts yielded 15.6 g (100%) of colorless oily 2-benzoyl-5-methyl-2,5-diazabicyclo[2.2.2]octane that was homogeneous by thin layer chromatography. It was characterized as the oxalate salt, melting point 167°-169° (dec.).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>CCOCC.C1COCC1>[CH2:9]([N:16]1[CH:17]2[CH2:23][CH2:22][CH:21]1[CH2:20][C:19]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:24])[CH2:18]2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2)CC2CCC(C1)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of phenylmagnesium bromide in ether (3 M, 2.3 mL) was added dropwise to a solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (1.0 g, 4.6 mmol) in THF (20 mL) that had been cooled to 0° C. The mixture was stirred for 3 hours and a solution of saturated aqueous ammonium chloride was added and the products extracted into diethyl ether, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 10-30% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.5 g) as an oil. LCMS m/z 294.4 [M+H]+. R.T.=2.59 min (Analytical Method 4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][OH:30])[CH:23]=2)[C:9]1=[O:31].[CH2:32]([N:34]([CH2:45][CH3:46])[CH2:35][CH2:36][O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH3:33]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:42][C:41]3[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][N:34]([CH2:45][CH3:46])[CH2:32][CH3:33])=[CH:44][CH:43]=3)=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][OH:30])[CH:23]=2)[C:9]1=[O:31]
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCO)c1)C(=O)N(c1ccccc1Br)C2
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCO)c2)C(=O)N(c2ccccc2Br)C3)cc1
Temperature: 180 °C
Yield: 17.8 %

Procedure:
200 mg (0.40 mmol) of 3-(2-bromophenyl)-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one was treated with 250 mg (1.2 mmol) of 4-[2-(diethylamino)ethoxy]aniline and the mixture heated at 180° C. for 40 minutes. The mixture was cooled and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 45 mg (18%) of 3-(2-bromophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 98° C.
Reaction SMILES: Br[C:2]([CH3:12])([CH3:11])[C:3]([NH:5][C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[O:4].[Na+].[C:14]([O:17][CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[C@H:29]([NH:30][C:31](=[O:40])/[C:32](/[C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[N:33]\[OH:34])[C:28](=[O:41])[N:23]2[C:24]=1[C:25]([O-:27])=[O:26])(=[O:16])[CH3:15].CCO.C([O-])(=O)C>CS(C)=O>[C:14]([O:17][CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[C@H:29]([NH:30][C:31](=[O:40])/[C:32](=[N:33]\[O:34][C:2]([C:3]([NH:5][C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[O:4])([CH3:12])[CH3:11])/[C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)[C:28](=[O:41])[N:23]2[C:24]=1[C:25]([OH:27])=[O:26])(=[O:16])[CH3:15]
Reactant: CN(C)C(=O)NC(=O)C(C)(C)Br
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3ccco3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NC(=O)N(C)C)c3ccco3)[C@H]2SC1
Yield: 59 %

Procedure:
This compound was prepared from 1-(2-bromo-2-methylpropionyl)-3,3-dimethylurea and (6R,7R)-3-acetoxymethyl-7-[Z-2-(fur-2-yl)-2-hydroxyiminoacetamido]-ceph-3-em-4-carboxylic acid sodium salt by the method described in Example 1. λmax (EtOH) 275 nm (ε 16,500), νmax (Nujol) 3260 (NH), 3700-2100 (bonded OH), 1788 (β-lactam), 1735 (acetate), 1720 (--CO2H), 1670, 1540 cm-1 (--CONH), τ (DMSO d6) 7.09 (N(Me)2), 0.97 (--CONHCO--), 8.5 (C(Me)2), 2.06, 3.28, 3.16 (furyl), 0.18 (CONH), 4.01 (7 H), 4.71 (6 H), 6.25, 6.46 (2--CH2 --), 4.97, 5.29 (3--CH2 --), 7.98 (CH3CO). Yield: 59%.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])(=[O:5])[CH3:4]>CO>[CH3:16][C:12]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]2[CH:7]=[C:6]([C:3](=[O:5])[CH:4]=[CH:3][C:6]3[CH:7]=[CH:8][C:13]([CH3:12])=[CH:14][CH:15]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C=CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 8 h
Yield: 191.4 %

Procedure:
10 g of 50% strength sodium hydroxide solution were added dropwise to a solution of 50 g (0.22 mole) of 6-acetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene and 26.1 g (0.22 mole) of 4-tolylaldehyde in 250 ml of methanol. The mixture was stirred overnight, after which is was poured onto ice/water and left to stand for several hours. The precipitated crystals were filtered off under suction and dried to give 70 g of 1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-3-(4-tolyl)-prop-2-en-1-one of melting point 153°-154° C.
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].CCN(C(C)C)C(C)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[C:25]([N:1]1[C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1CCC2(CCOCC2)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCC2(CCOCC2)N1C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
To a solution of ethyl 8-oxa-1-azaspiro[4.5]decane-2-carboxylate (166) (135 mg, 0.63 mmol) in anhydrous dichloromethane (2 mL) was added Hunig's base (0.22 mL, 1.3 mmol) followed by acetyl chloride (0.05 mL, 0.76 mmol) and the reaction stirred at room temperature under nitrogen for 1.5 h. The reaction was diluted with dichloromethane and washed with 0.1 N HCl and the organic layer dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 60-100% hexanes/EtOAc to afford the title compound as a yellow oil (94 mg, 58% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([NH2:20])[CH3:19])[CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].CS([C:26]1[N:31]=[C:30]([N:32]2[CH2:37][CH2:36][C:35](=[O:38])[N:34]3[CH2:39][CH:40]=[C:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:42]=[C:33]23)[CH:29]=[CH:28][N:27]=1)(=O)=O.O>CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([CH3:10])([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([NH:20][C:26]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][C:35](=[O:38])[N:34]4[CH2:39][CH:40]=[C:41]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[N:42]=[C:33]34)[CH:29]=[CH:28][N:27]=2)[CH3:19])[CH:12]=1)[CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)c1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Reactant: CC(N)Cc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(Cc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Temperature: 100 °C

Procedure:
To a mixture of {1-[3-(2-amino-propyl)-phenyl]-1-methyl -ethyl}-carbamic acid tert-butyl ester (0.19 g, 0.65 mmol) and 1-(2-methanesulfonyl-pyrimidin-4-yl) -8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (0.26 g, 0.72 mmol) in NMP (2 mL) was heated to 100° C. for 17 h. The mixture was poured into water (15 mL) and extracted with ethyl acetate. The organic extracts were combined, washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and chromatographed on silica gel using 0-4% MeOH/CH2Cl2 to afford a light yellow oil. M+1=596.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH2:10][C:11]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:9]([CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[CH2:10][C:11]([NH:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: O=C(CNCc1cccc(Br)n1)NC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CC(=O)NC1CCCC1)Cc1cccc(Br)n1
Temperature: 0 °C

Procedure:
N2-[(6-Bromopyridin-2-yl)methyl]-N-cyclopentylglycinamide (Example 187, Step 1) (0.25 g, 0.80 mmol) was dissolved in dichloromethane (3.2 mL) and triethylamine (0.34 mL, 2.4 mmol) was added and the reaction was cooled to 0° C. Acetyl chloride (0.06 mL, 0.88 mmol) was added and the reaction was allowed to warm to room temperature and stir to completion. The solution was diluted with dichloromethane, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by reverse phase HPLC to yield the title compound.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])O[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH3:17]>>[CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:17][C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: N
Reactant: CCCCCCCc1c(C)oc(C)cc1=O
Product: CCCCCCCc1c(C)[nH]c(C)cc1=O
Temperature: 25 °C

Procedure:
Compound 1 (0.01 g, 30.6 mmol) was heated at 100° C. with aqueous ammonia in a high pressure tube for 18 h. After the mixture was cooled to room temperature, the crude was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 5:1 ethyl acetate/methanol gave 3-heptyl-2,6-dimethylpyridin-4(1H)-one (3) as a brown solid: yield 0.083 g (81%); silica gel TLC Rf 0.25 (3:1 ethyl acetate/methanol); 1H NMR (CD3OD) δ 0.68-0.71 (m, 3H), 1.09-1.28 (m, 10H), 2.20 (s, 3H), 2.27 (s, 3H), 2.34-2.36 (m, 2H) and 6.29 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:21]=[CH:20][C:9]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1)([OH:3])=[O:2].[OH:22]O.Cl>[OH-].[Na+]>[C:1]([CH2:4][CH2:5][C:6]1[CH:21]=[CH:20][C:9]([CH:10]2[O:22][CH:11]2[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCc1ccc(C=CC(=O)c2ccccc2)cc1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccc(C2OC2C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a suspension of 5.6 g of 4-(2-carboxyethyl)benzalacetophenone and 20 ml of 1N sodium hydroxide solution was added 4 ml of 30% hydrogen peroxide at room temperature. The mixture was cooled in an ice-bath and 15 ml of 0.5N sodium hydroxide solution was added dropwise over a few min. with stirring. The reaction mixture was stirred at room temperature for 3 hrs. and then the pH was adjusted from 9.4 to 4.5 by the addition of 1N hydrochloric acid. After about 1/2 hr., the precipitate was collected. The precipitate was dissolved in 200 ml of ethyl acetate, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated. The residue was dissolved in 100 ml of boiling ethyl acetate. About 50 ml of the solvent was evaporated and 50 ml of ether was added. The solution was concentrated to about 25 ml and after standing at room temperature for 17 hrs., the solid was collected, washed with 1:4-ethyl acetate-ether followed by ether and dried under vacuum at 60°-65°C to give 3.3 g (55%) of 3-[4-(2-carboxyethyl)phenyl]-1-phenyl-2,3-epoxy-1-propanone as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Br)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-5-methoxybenzoic acid (231 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 2-bromo-5-methoxybenzoyl chloride.
Reaction SMILES: [CH2:1]([C@@H:3]1[C@@H:7]([OH:8])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1)[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C@@H:3]1[C@@H:7]([O:8][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
(3S,4R)-benzyl 3-ethyl-4-hydroxypyrrolidine-1-carboxylate (18.9 g, 76 mmol), 4-methylbenzene-1-sulfonyl chloride (21.68 g, 114 mmol) were dissolved in DCM (100 mL) and cooled in an ice bath. Added N,N-dimethylpyridin-4-amine (1.852 g, 15.16 mmol) and triethylamine (11.51 g, 114 mmol) and let the reaction mixture warm to RT overnight. The suspension was passed over a silica column and eluted with Heptanes/EA (9:1 to 4:1 mixtures) to give (3S,4R)-benzyl 3-ethyl-4-(tosyloxy)pyrrolidine-1-carboxylate (28.7 g, 71.1 mmol, 94% yield). LCMS:M+1=404, t=3.07 min.