Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)[C:5]([OH:7])=O.C(Cl)(C(Cl)=O)=O.[NH2:25][C:26]1[C:27]([F:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C1COCC1.O.CN(C=O)C>[F:34][C:27]1[C:28]([OH:33])=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=[C:2]([F:1])[C:3]=1[CH3:18]
Reactant: Cc1c(F)cc(-c2cccc(F)c2)cc1C(=O)O
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(F)cc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
To a solution of 3-fluoro-5-(3-fluorophenyl)-2-methyl-benzoic acid (1.1 g, 4.4 mmol, 1 eq) in CH2Cl2 (15 mL) at 0° C. was added DMF (0.05 mL), and (COCl)2 (1.68 g, 13.2 mmol, 3 eq). The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated to dryness under reduced pressure and the residue obtained dissolved in THF (10 mL) and added dropwise to a solution of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (770 mg, 5.3 mmol, 1.2 eq) and K2CO3 (3 g, 22.1 mmol, 5 eq) in THF (20 mL) at 0° C. After the addition, the reaction mixture was stirred for 2 h and then water added and the aqueous layer extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 10:1 to 3:1) to give the title compound as a white solid (0.9 g, 54%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C@@H:10]1[C@H:15]([N:16]=[N+]=[N-])[CH2:14][C@H:13]2[CH2:19][C@@H:11]1[C:12]2([CH3:21])[CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C@@H:10]1[C@H:15]([NH2:16])[CH2:14][C@H:13]2[CH2:19][C@@H:11]1[C:12]2([CH3:21])[CH3:20]
Reactant: CC1(C)[C@H]2C[C@@H](N=[N+]=[N-])[C@@H](CCOC3CCCCO3)[C@@H]1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1(C)[C@H]2C[C@@H](N)[C@@H](CCOC3CCCCO3)[C@@H]1C2
Temperature: 0 °C
Yield: 96 %

Procedure:
To a solution of 8.64 g of the above-mentioned azide compound 15 in 300 ml of ether is portionwise added 1.2 g of lithium aluminum hydride and the mixture is refluxed under heating for 1 hour. To the reaction mixture is added 10 g of ice and then added 300 ml of 10% aqueous solution of sodium hydroxide. The resulting mixture is shaken well and then the ether layer is collected. The aqueous layer is extracted with ether again. The combined ether layers are washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give 7.56 g of the titled compound 16, of which the physical constant is as follows.
Reaction SMILES: CC(C)=O.[Br:5][C:6]1[N:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][N:11]=1
Reactant: ClCCN1CCCC1
Reactant: Oc1ccc(Br)nc1
Agent: Cl
Solvent: CC#N
Solvent: CC(C)=O
Product: Brc1ccc(OCCN2CCCC2)cn1

Procedure:
The product is obtained analogously to Example 3.1 e (1:1 mixture of acetone:acetonitrile instead of DMF) from 3.90 g (22.4 mmol) 6-bromo-pyridin-3-ol and 4.25 g (25.0 mmol) N-(2-chloroethyl)-pyrrolidine hydrochloride.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][CH2:46][OH:47])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][CH2:46][OH:47])[CH2:39][CH2:40]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OCCCN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCO)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 3-piperazin-1-yl-propan-1-ol (Acros) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C35H45N6O3Cl2 [(M+H)+] 667.2925, observed 667.2923.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13](F)[C:12]([C:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH:21]=3)=[C:11]([F:29])[CH:10]=2)[CH2:4]1.N(C[C@@H]1OC(=O)N(C2C=CC(C3CCN(CC4C=CC=CC=4)CC=3)=C(F)C=2)C1)=[N+]=[N-]>>[NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH:21]=3)=[C:11]([F:29])[CH:10]=2)[CH2:4]1
Reactant: NC[C@H]1CN(c2cc(F)c(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Product: NC[C@H]1CN(c2ccc(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1

Procedure:
The procedure was identical to that used for Intermediate 54, except (5R)-5-(azidomethyl)-3-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl]-1,3-oxazolidin-2-one (WO 0181350 A1) (21.19 g, 52.00 mmol) was used as starting material. 13 g of the title product was obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([NH2:22])[CH:19]=[N:18]2)=[CH:13][CH:12]=1.[OH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[OH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:22][C:20]2[CH:19]=[N:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][C@H:2]4[CH3:1])=[CH:12][CH:13]=3)[CH:21]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(N)cn2)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(NC(=O)c3ccc(O)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-ylamine obtained in Example 29-(1) (0.191 g), 4-hydroxybenzoic acid (0.097 g), 1-hydroxybenzotriazole monohydrate (0.107 g) and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (0.18 g) in chloroform (6.4 mL) was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-type silica gel column chromatography (eluting solvent: chloroform→chloroform:methanol=10:1) to give the titled compound (0.137 g) as a colorless amorphous substance.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([C:18]([CH3:36])([CH3:35])[C:19]([N:21]([C@H:23]2[C@H:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][NH:25][CH2:24]2)[CH3:22])=[O:20])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.N1CCCC1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:17][C:14]([F:15])([F:16])[C:12]1[CH:11]=[C:10]([C:18]([CH3:35])([CH3:36])[C:19]([N:21]([C@H:23]2[C@H:27]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:26][N:25]([C:3](=[O:4])[CH2:2][Br:1])[CH2:24]2)[CH3:22])=[O:20])[CH:9]=[C:8]([C:7]([F:38])([F:37])[F:6])[CH:13]=1
Reactant: O=C(Cl)CBr
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)CBr)C[C@H]1c1ccc(F)cc1
Yield: 70 %

Procedure:
To a stirred solution of bromo-acetyl chloride (0.80 g, 4 mmol) in CH2Cl2 (5 ml) at 0° C. was added over 1 hour a solution of rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-N-methyl-isobutyramide (pyrrolidine interm. VII-4 described herein above, 0.94 g, 1.97 mmol) and ethyl-diisopropyl-amine (0.37 ml, 2.17 mmol) in CH2Cl2 (10 mL). The reaction was stirred over night, quenched by addition of an aqueous solution of NaHCO3, and the product extracted with CH2Cl2. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 0.83 g (70%) of rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-[(3S,4R)-1-(2-bromo-acetyl)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-N-methyl-isobutyramide as a white foam.
Reaction SMILES: [NH2:1][C@:2]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[C:20]([NH:22][CH2:23][C@H:24]3[CH2:26][C@@H:25]3[CH3:27])[N:19]=[C:18]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])[CH:17]=2)=[N:13][CH:12]=1)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C(=O)N([Cl:41])C(=O)C1>C(Cl)Cl>[NH2:1][C@:2]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[C:20]([NH:22][CH2:23][C@H:24]3[CH2:26][C@@H:25]3[CH3:27])[N:19]=[C:18]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:30])=[O:31])[C:17]=2[Cl:41])=[N:13][CH:12]=1)([CH3:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H]1C[C@@H]1CNc1cc(-c2ncc([C@](C)(N)Cc3ccccc3)o2)cc(N(C)S(C)(=O)=O)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: C[C@H]1C[C@@H]1CNc1cc(-c2ncc([C@](C)(N)Cc3ccccc3)o2)c(Cl)c(N(C)S(C)(=O)=O)n1
Reaction time: 15 h

Procedure:
To a solution of N-[4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3-oxazol-2-yl}-6-({[(1S,25)-2-methylcyclopropyl]methyl}amino)pyridin-2-yl]-N-methylmethanesulfonamide (0.009 g, 0.015 mmol) in 0.3 mL CH2Cl2 was added 0.09 mL of a 0.15M stock solution of NCS in CH2Cl2. After 15 h, a further 0.10 mL CH2Cl2 and 0.1 mL 0.15 M stock solution of NCS in CH2Cl2 were added. After 24 h, the reaction was concentrated, redissolved in DMF and purified by preparative HPLC to afford N-[4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3-oxazol-2-yl}-3-chloro-6-({[(1S,2S)-2-methylcyclopropyl]methyl}amino)pyridin-2-yl]-N-methylmethanesulfonamide as a yellow solid. 1H NMR (400 MHz, d4-MeOH) δ 7.30-7.29 (m, 3H), 7.24 (s, 1H), 7.04-7.02 (m, 3H), 3.47 (d, J=13.3 Hz, 1H), 3.28 (s, 3H), 3.26-3.20 (m, 5H), 1.71 (s, 3H), 1.06 (d, J=5.9 Hz, 3H), 0.85 (m, 1H), 0.71 (m, 1H), 0.43 (m, 1H), 0.27 (m, 1H). LCMS (M+H)=505 (chlorine pattern).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22](Br)[CH2:23][CH3:24].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)[CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2cc(Br)ccc2C1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(Br)ccc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
((S)-6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (12.2 g, 37.4 mmol) was dissolved in N,N-dimethylformamide (1000 ml). Sodium hydride (50% in oil) (1.975 g, 41.14 mmol) was added and stirred for 15 minutes at room temperature. Propyl bromide (3.74 ml, 41.14 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of ice and H2O (400 ml) and twice extracted with 200 ml diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield 14.4 g of crude product. The crude product was purified with silica gel chromatography with cyclohexane/ethyl acetate (95:5) as eluent, yielding the purified product (10.5 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[C@:3]2([CH3:13])[O:12][C@H:6]([C:7](Cl)(Cl)[C:8]=1[Cl:9])[CH:5]=[CH:4]2.CC(C)=[O:16].C(=O)(O)[O-].[Na+]>[N+]([O-])([O-])=O.[Ag+].O>[Cl:9][C:8]1[C:7](=[O:16])[C@@H:6]2[O:12][C@:3]([CH3:13])([C:2]=1[Cl:1])[CH:4]=[CH:5]2
Reactant: C[C@]12C=C[C@H](O1)C(Cl)(Cl)C(Cl)=C2Cl
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: C[C@@]12C=C[C@@H](O1)C(=O)C(Cl)=C2Cl
Temperature: 65 °C

Procedure:
Silver nitrate (166 g, 0.982 mol) is added to a stirred mixture of (1R*,5S*)-2,3,4,4-tetrachloro-1-methyl-8-oxabicyclo[3.2.1]octa-2,6-diene (83 g, 0.491 mol), acetone (1500 ml) and water (1500 ml) and the mixture is heated at 65° C. for 16 hours. The reaction mixture is cooled to room temperature, and a saturated solution of aqueous sodium bicarbonate is added to adjust the pH to 7-8. The mixture is filtered through a plug of diatomaceous earth, and the filtrate is concentrated in vacuo to remove most of the acetone. The aqueous mixture is extracted with ethyl acetate (3×500 ml) and the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated. The residue is purified by flash column chromatography on silica gel to give (1R*,5S*)-3,4-dichloro-5-methyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one (29.5 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=[CH:27][N:26]=1.[CH2:37]([O:39][C:40](=[O:56])[CH:41]([O:43][P:44]([CH2:53][CH:54]=O)([O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:45])[CH3:42])[CH3:38].[BH3-]C#N.[Na+]>C(O)(=O)C.CN(C=O)C>[CH2:37]([O:39][C:40](=[O:56])[CH:41]([O:43][P:44]([CH2:53][CH2:54][N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:9](=[O:23])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:24][C:25]4[N:30]=[C:29]([C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)[CH:28]=[CH:27][N:26]=4)[CH:4]=3)=[CH:15][CH:14]=2)[CH2:22][CH2:21]1)([O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:45])[CH3:42])[CH3:38]
Reactant: CCOC(=O)C(C)OP(=O)(CC=O)Oc1ccccc1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)OP(=O)(CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1)Oc1ccccc1
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
A solution of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide (20 mg, 0.04 mmol) and 2-[(2-oxo-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester (60 mg, 0.2 mmol) in 1% Acetic Acid/DMF (1.5 mL) solution was stirred at room temperature for 7 hours followed by an addition of NaCNBH3 (30 mg, 0.24 mmol). The resulting mixture was stirred for additional 30 min when completion of the reaction was observed by LCMS. After evaporation of solvent, the residue was taken up in CH2Cl2 and then extracted with saturated aqueous NaHCO3 The organic extracts were dried in vacuo and the residue was purified by silica gel chromatography using MeOH—CH2Cl2 (7%) to afford 8 mg (26%) of the product. 31P NMR (121.4 MHz, CDCl3) δ 27.2, 28.6; MS (m/z) 764 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([N:11]1[CH2:12][CH2:13][C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)([O:14][CH3:15])[CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC1(c2ccc(F)c(F)c2)CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Yield: 54.9 %

Procedure:
Preparation according to Preparation 14. 3-(3,4-Difluorophenyl)-3-methoxypyrrolidine (1.15 g, 5.4 mmol), dry dimethyl formamide (5 mL), sodium hydride (60% dispersion in mineral oil, 0.259 g, 6.48 mmol). Benzylbromide (0.642 mL, 5.4 mmol) in dry dimethyl formamide (5 mL). Work up according to Preparation 14. Purification by flash column chromatography on silica gel (ethyl acetate) gave the title compound (0.9 g, 55%). MS m/z (rel. intensity, 70 eV) 288 (12), 273 (14), 133 (53), 132 (30), 91 (bp).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16]C(OC(C)(C)C)=O)=[CH:11][C:10]=1[P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][C:10]=1[P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1ccc(CNC(=O)OC(C)(C)C)cc1P(=O)(OCC)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)c1ccc(CN)cc1P(=O)(OCC)OCC
Reaction time: 3 h

Procedure:
[4-(tert-Butoxycarbonylamino-methyl)-2-(diethoxy-phosphoryl)-phenyl]-phosphonic acid diethyl ester (2.0 g, 4.2 mmol) was dissolved in TFA/CH2Cl2 (25%, 20 mL) and stirred for 3 h. The mixture was evaporated under a stream of N2, dissolved in EtOAc and washed with sat'd NaHCO3. The organic layer was dried over magnesium sulfate, and concentrated to a brown oil (0.9 g, 2.3 mmol) which was used without purification in the next reaction.
Reaction SMILES: [CH:1]1([N:7]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([O:16]C)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1.CCO.O>[CH:1]1([N:7]([CH2:18][CH:19]2[CH2:20][CH2:21]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of methyl 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylate (Intermediate 12, 4.14 g; 14.3 mmol) in THF/EtOH/H2O (3/2/1, 120 ml) was treated with an aqueous solution of lithium hydroxide monohydrate (42.9 ml; 1.00 M; 42.9 mmol) at ambient temperature. After 1 hour, the organic solvents were evaporated in vacuo, the remaining aqueous layer was acidified with HCl (1 N) until pH=6 and extracted with DCM (4×50 ml). The combined organic layers were dried over MgSO4 and evaporated to dryness to give the title compound as an off-white solid (3.64 g, 92.5%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:11][C@@H:12]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)[CH2:13][OH:14].C(N(CC)CC)C.CCOC(C)=O.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:11][C@@H:12]([CH:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)[CH2:13][OH:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: N[C@H](CO)C1Cc2ccccc2C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=S(=O)(N[C@H](CO)C1Cc2ccccc2C1)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
5-Chlorothiophene-2-sulfonyl chloride (0.856 g, 3.94 mmol) was added dropwise (5 min) as a solution in CH2Cl2 (5 mL) to a 0° C. solution of (2S)-2-amino-2-(2,3-dihydro-1H-inden-2-yl)ethanol (0.46 g, 2.63 mmol) in CH2Cl2 (5 mL and triethylamine (3.8 mL, 5.26 mmol). The solution was allowed to warm to 25° C. overnight (19 h). An aliquot was taken and TLC. (1:1 EtOAc-hexane) indicated that reaction was complete. It was diluted with CH2Cl2 (50 mL) and the organic layer was washed with 1N HCl (2×50 mL), saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude oil (0.89 g). The crude product was purified by column chromatography, silica gel 230-400 mesh, eluant: 1:4 EtOAc-hexane to afford 5-chloro-N-[(1S)-1-(2,3-dihydro-1H-inden-2-yl)-2-hydroxy ethyl]thiophene-2-sulfonamide as an amorphous white solid (0.361 g, 38.4%). Mass Spectrum (−ESI): 356 (M−H)−. Anal. Calc'd for C15H10ClNO3S2: C, 50.34 H, 4.51 N, 3.91 Found: C, 50.28 H, 4.36 N, 3.77.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1.[C:20]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:20])[C:7](=[O:12])[C@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC[C@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reaction time: 12 h
Yield: 84.8 %

Procedure:
(7S)-2-Chloro-8-cyclopentyl-7-ethyl-5,7-dihydropteridin-6-one 41e (2.80 g, 10 mmol) was dissolved in 50 mL of acetone followed by the addition of methyl p-toluenesulfonate (2.80 g, 15 mmol) and potassium carbonate (2.76 g, 20 mmol) successively, stirred for 12 hours. The resulting solution was added with 50 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure, The resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound (7S)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one 41f (2.50 g, yield: 85.0%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([O:21][CH3:22])=[O:20])[C:11]=1[CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:1][C:2]1[C:7]([NH:8][CH2:12][C:11]2[C:14]([NH:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=[CH:17][C:10]=2[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)Nc1cccc(C)c1CCl
Reactant: Nc1cccnc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Nc1cccc(C)c1CNc1cccnc1N
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
To a solution of 2,3-diaminopyridine (1.09 g) in methanol (22 ml) was added 2-methyl-6-methoxycarbonylaminobenzyl chloride (2.14 g) and potassium carbonate (1.38 g) at room temperature and the mixture was stirred for 1.5 hours. The insoluble material was removed by filtration and methanol in the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (30 g) and eluted with a mixture of chloroform and methanol (100:1) to give a crystalline product. The crystals were triturated with diisopropyl ether to give 2-amino-3-(2-methyl-6-methoxycarbonylaminobenzylamino)pyridine (1.44 g).
Reaction SMILES: C(OC(C)CC(C)C)(=O)C.[C:11]([O:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16]CCC)(=[O:13])[CH3:12]>>[CH3:16][CH:15]([O:14][C:11]([CH3:12])=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCC(OC(C)=O)c1ccccc1
Agent: CC(=O)OC(C)CC(C)C
Agent: *CC(*)C
Product: CC(=O)OC(C)c1ccccc1

Procedure:
100 Pounds of polypropylene are heated to about 300° F. 15 Pounds of 2-methyl-4-pentanol acetate prepared according to Example IV (bulked fractions 4-6) are added to the liquified polypropylene. The procedure is carried out in the apparatus shown in FIGS. 9 and 10. After mixing for about 8 minutes, the valve "V" is opened to allow the exit of polypropylene mixture which has been treated with the phenylpentanol acetate, whereby solid pellets having pronounced aromas described as "green, vegetative, styrallyl acetate-like" are formed on the conveyor. The pellets thus obtained are then admixed with about 20 times their weight of unscented polypropylene and untreated polypropylene and the mixture is heated and molded into "spaghetti" tows. The "spaghetti" tows are cut into small cylinders approximately 0.1 inches in length×0.2 inches in diameter. The cylinders have strong and pleasant aromas as described, supra.