Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[Cl:16][C:17]1[C:18]([CH3:32])=[C:19]([C:30]#[N:31])[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:21][C:22]=1[CH3:23].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[Cl:16][C:17]1[C:18]([CH3:32])=[C:19]([C:30]#[N:31])[C:20]([N:24]2[CH2:25][CH2:26][N:27]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:28][CH2:29]2)=[N:21][C:22]=1[CH3:23]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1nc(N2CCNCC2)c(C#N)c(C)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)c(C#N)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.7 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (25 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (16 μl, 0.18 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of 5-chloro-4,6-dimethyl-2-piperazin-1-yl-pyridine-3-carbonitrile (38 mg, 0.15 mmol) and DIPEA (79 μl, 0.45 mmol) in anhydrous DCM (2 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 2.7 mg of a solid (0.007 mmol, 5%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:49]=[CH:48][C:39]([C:40]([NH:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])=[O:41])=[CH:38][CH:37]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:49]=[CH:48][C:39]([C:40]([NH:42][CH2:43][CH2:44][N:45]([CH3:46])[CH3:47])=[O:41])=[CH:38][CH:37]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CN(C)CCNC(=O)c1ccc(N)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN(C)CCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(F)(F)C(=O)N3C)cc1
Yield: 66.8 %

Procedure:
A mixture of 0.0562 g (0.18 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0514 g (0.27 mmole) of toluenesulfonic acid monohydrate, 0.0373 g (0.18 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 15.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (80:20:1) to give 0.0603 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-benzamide (I-264)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1cnn(-c2ccccc2[N+](=O)[O-])c1N
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)c1cnn(-c2ccccc2N)c1N
Temperature: 25 °C

Procedure:
1.28 g (5.27 mmol) of 5-amino-1-(2-nitrophenyl)-1H-pyrazole-4-carboxamide (Example 21A) are introduced into 30 ml of ethyl acetate and stirred with 5.8 g (25.8 mmol) of tin(II) chloride dihydrate at 70° C. for 16 hours. After cooling to room temperature, the solution is adjusted to pH 9-10 with saturated sodium bicarbonate solution. The tin salts precipitated thereby are filtered off through kieselguhr. The filtrate is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution. After drying over sodium sulphate, the solvent is removed in vacuo. 0.82 g (72% of theory) of the desired product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>CO>[C:12]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(CO)ccc1N
Solvent: CO
Product: COc1cc(CO)ccc1NC(C)=O
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of 4-amino-3-methoxybenzyl alcohol (900 mg) in methanol was added acetic anhydride (1.8 g) under ice cooling, and the mixture was stirred for 1 hour at the same temperature. After evaporation, the residue was dissolved in ethyl acetate, and the solution was washed with sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated in vacuo to give 4-acetamido-3-methoxybenzyl alcohol (840 mg) as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:33])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31](O)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:36]1([S:42]([N:45]=[C:46]=[O:47])(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:33])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([C:46](=[O:47])[NH:45][S:42]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)(=[O:43])=[O:44])[C:19]=4[CH2:18]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 39.5 %

Procedure:
To a solution of the compound of Example 44 (0.511 g, 1.1 mmol) in dry THF (20 mL) was added sodium hydride (60% in mineral oil, 48 mg, 1.2 mmol), and the slurry heated at 40° C. under argon with stirring for 20 minutes. Phenylsulfonylisocyanate (160 μL, 1.2 mmol) was added and the mixture was stirred for 14 hours. The solvent was then removed by rotary evaporation to give the crude product. The solid material was washed twice with 20 mL CH2Cl2, and then twice with 20 mL MeoH:CH2Cl2(1:1) to give the title compound (274 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O-:10].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:2]2[CH:7]=[CH:6][C:5]([CH:9]=[O:10])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 127.3 %

Procedure:
4-Chlorophenol (22.6 g) was added to a stirred solution of sodium methoxide (9.5 g) in methanol (80 ml). After 30 min the solvent was evaporated in vacuo. Residual traces of methanol were removed by addition of toluene and evaporating again in vacuo. The residue was taken up in DMF (200 ml) and 4-fluorobenzaldehyde (19.85 g) added. The mixture was stirred and heated at 120° for 4 hr, cooled, poured into water and extracted with toluene (2×200 ml). The combined extracts were washed with water, 2M sodium hydroxide and satd. brine, dried over magnesium sulphate and concentrated to leave a brown oil. Distillation gave the title compound (26.03 g), b.p.=140°-50°/0.5 mm.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:14]1[O:22][C:21]2[C:16](=[C:17]([CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:18]=[CH:19][CH:20]=2)[O:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[O:1]=[C:2]1[C:11]([CH2:12][N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[O:22][CH2:14][O:15][C:16]=34)[CH2:26][CH2:27]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: c1cc(CCC2CCNCC2)c2c(c1)OCO2
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2cc1CN1CCC(CCc2cccc3c2OCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.9 %

Procedure:
In 50 ml of tetrahydrofuran were dissolved 0.24 g of 2-oxo-1,2-dihydro-3-quinolinecarboxaldehyde and 0.3 g of 4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine. To the mixture were added 0.5 ml of acetic acid and 0.42 g of sodium triacetoxyborohydride were added thereto, followed by stirring at room temperature for 12 hours. An aqueous saturated sodium bicarbonate aqueous solution was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting solid was collected by filtration, to give 130 mg of the title compound as a light brown solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:26]C(=O)OC(C)(C)C)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C@H:8]([NH2:26])[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC(Oc2ccc(F)c(F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCC(Oc2ccc(F)c(F)c2)CC1
Yield: 106.5 %

Procedure:
The product from Example 5, Step (a) (1.2 g) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (5 ml) was added. After 1 hr at room temperature the solution was evaporated and aqueous NaOH (2M) added. The product was extracted with ethyl acetate, the combined organic extracts dried, filtered and concentrated to give the sub-title product as an oil (1 g).
Reaction SMILES: O[CH:2]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)[C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30]>CCCCCC.C(OCC)(=O)C>[CH:37]([C:34]1[CH:35]=[CH:36][C:31]([CH2:2][C:3]2[C:11]3[O:10][CH2:9][CH:8]([C:12]4[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=4)[C:7]=3[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=2[CH3:30])=[CH:32][CH:33]=1)([CH3:38])[CH3:39]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(O)c1ccc(C(C)C)cc1)OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(Cc2ccc(C(C)C)cc2)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 64 %

Procedure:
Using N-(7-(hydroxy(4-isopropylphenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 95, the title compound was synthesized in the same manner as in Example 96. Yield: 64%. Melting point: 157-158° C. (hexane-ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:27])[CH2:25][NH2:26])[CH2:19]2)=[CH:15][CH:14]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:27])[CH2:25][NH:26][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=3)[CH2:19]2)=[CH:15][CH:14]=1
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccc(F)c(F)c1)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The chloroform (0.4 mL) solution of 3,4-difluorobenzoyl chloride (0.060 mmol) was added to the chloroform (1.0 mL) solution of the (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and triethylamine (0.070 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, and then mixed with a (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol). The mixture was stirred at room temperature for 12 hours, and filtered. The resin was washed with dichloromethane (0.5 mL). The filtrate and the washings were combined and mixed with dichloromethane (4 mL). The solution was washed with a 2M NaOH aqueous solution (0.5 mL), and then concentrated to obtain the (R)-1-(4-chlorobenzyl)-3-[{N-(3,4-difluorobenzoyl)glycyl}amino]pyrrolidine (Compd. No. 69) (7.8 mg, 38%): the purity was determined with RPLC/MS (>99%); ESI/MS m/e 408.0 (M++H, C20H20ClF2N3O2).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[NH2:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[CH3:25][C:22]1([CH3:26])[CH2:21][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)[C:24]=2[O:23]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: CC1(C)Cc2cccc(N)c2O1
Product: CC1(C)Cc2cccc(Nc3ccc4c(N)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=306.1 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4).
Reaction SMILES: [C:1]12(O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C)C=O.[H-].[Na+].[C:19]([N:29]1[CH2:37][C@H:36](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:35][C@H:30]1[C:31]([O:33][CH3:34])=[O:32])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C1C=CC=CC=1>[C:19]([N:29]1[CH2:37][C@@H:36]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)[CH2:35][C@H:30]1[C:31]([O:33][CH3:34])=[O:32])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](C23CC4CC(CC(C4)C2)C3)CN1C(=O)OCc1ccccc1

Procedure:
A solution of 5.3 g. (0.035 mole) of 1-adamantanol in 40 ml. of dimethylformamide and 80 ml. of benzene is treated with 1.6 g. of sodium hydride (50% dispersion in mineral oil). The mixture is refluxed for 15 minutes, cooled, and treated with 7.5 g. (0.017 mole) of N-carbobenzyloxy-trans-4-tosyloxy-L-proline, methyl ester. The resulting reaction mixture is stirred and refluxed for four hours, cooled, and the solvent removed under reduced pressure. The residue is dissolved in 100 ml. of chloroform and then washed with 25 ml. of water (3 times). The organic phase is dried (MgSO4), filtered, and the solvent evaporated to give N-carbobenzyloxy-cis-4-(1-adamantyl)-L-proline, methyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:3]1.[Br:13]Br.CO>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:13][C:5]1[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: Cn1ccc(-c2ccncc2)n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1cc(Br)c(-c2ccncc2)n1
Reaction time: 4 h

Procedure:
To a solution of 4-(1-methyl-1H-pyrazol-3-yl)pyridine 2.98 g; Example 3, Step 2) in 50 mL chloroform cooled in ice, was added dropwise, a solution of 1.15 mL bromine in 30 mL chloroform. About 15 mL methanol was added to help dissolution of the yellow precipitate that formed. After 4 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and diluted with dichloromethane. The dichloromethane layer was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated to yield the crude product as a yellow semisolid. The crude material was slurried in ethyl acetate and filtered through celite. The filtrate was evaporated to yield 4.18 g product as a yellow solid. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 240.5 by positive ESI.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[N-:14]=[N+:15]=[N-:16].[Na+].C1(C)C=CC=CC=1.[Cl-]>CN(C=O)C>[N:14]([CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)OCCC2Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)OCCC2N=[N+]=[N-]
Temperature: 80 °C

Procedure:
4-Chloro-7-cyanochroman (Step C) (8.1 g, 42 mmol) was dissolved in dry DMF (90 mL) and NaN3 (4.0 g, 62 mmol) was added and the reaction was heated to 80° C. under N2. After 5 h TLC (SiO2, toluene) showed that no starting chloride was present. The reaction was cooled and partitioned between EtOAc (200 mL) and H2O (150 mL). The organic phase was washed with H2O (2×100 mL) and brine (100 mL). The solution was dried over MgSO4, filtered and concentrated in vacuo to provide a residue which was purified by column chromatography (SiO2, 15% EtOAc in hexane) to provide the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:13][C:11]1[S:12][C:8]([NH2:7])=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[N:10]=1
Reactant: Cc1nc(-c2ccccc2C)c(NC(=O)OC(C)(C)C)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccccc2C)c(N)s1
Yield: 27.1 %

Procedure:
A solution of (2-methyl-4-o-tolyl-thiazol-5-yl)-carbamic acid tert-butyl ester (340 mg, 1.12 mmol, 1.0 equiv) in dichloromethane (10 mL) was treated with trifluoroacetic acid (0.7 mL, 9.00 mmol, 8.0 equiv) for 24 hours at ambient temperature. The mixture was concentrated under vacuum and the resultant residue dissolved in dichloromethane and washed sequentially with 10% aqueous potassium carbonate solution and saturated aqueous sodium chloride solution. The collected organic was dried over magnesium sulfate and filtered. The filtrate was passed through an Isolute® SCX-2 cartridge (eluting with dichloromethane, dichloromethane/methanol (1:1) and 2M ammonia in methanol) to afford 62.0 mg (27%) of 2-methyl-4-o-tolyl-thiazol-5-ylamine as a brown residue. LCMS (ESI) m+H=205.0; 1H NMR (400 MHz, CDCl3) δ: 7.33-7.18 (m, 4H), 3.54-3.45 (br, 2H), 2.58 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: C(OC[C:21]([O:26][CH3:27])([O:24]C)[CH2:22]O)CCCCCCCCCCCCCCCCC.[P:28](C(OCC)=O)([OH:31])([OH:30])=[O:29].N1C=CC=C[CH:38]=1>ClCCl>[P:28]([CH2:22][C:21]([O:26][CH2:27][CH3:38])=[O:24])([OH:31])([OH:30])=[O:29]
Reactant: CCOC(=O)P(=O)(O)O
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)(OC)OC
Reactant: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CP(=O)(O)O
Temperature: 25 °C

Procedure:
To a solution of 1-O-octadecyl-2,2-dimethoxy-1,3-propanediol (1.92 gm, 5 mmol) and ethyl phosphonoformate (1.19 g, 5 mmol) in dry pyridine (50 mL), cooled in an ice-salt bath, was added a solution of N,N-dicyclohexylcarbodiimide (3.1 g, 15 mmol) in dry dichloromethane (20 mL). The resulting mixture was stirred at room temperature over. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was flash chromatographed with a gradient of 0-10% methanol in dichloromethane to give the target compound. In a similar manner, use of ethyl phosphono-acetate resulted in the corresponding 1-O-octadecyl-2,2-dimethoxy-1,3-propane diol-3-ethylphosphonoacetate.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:13]=[C:12]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:8]=2[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+:32].C(C(C)=O)C(C)C>O>[CH:22]1([C:12]2[CH:13]=[C:14]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH:15]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]=2[C:9]([O-:11])=[O:10])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[Na+:32]
Reactant: O=C(O)c1c(C2CCCCC2)cc(C2CCCCC2)cc1C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C([O-])c1c(C2CCCCC2)cc(C2CCCCC2)cc1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A 300-mL eggplant shaped flask was charged with 2.0 g of 2,4,6-tricyclohexylbenzoic acid (prepared in Synthesis Example 1-5), 0.5 g of sodium hydrogencarbonate, 10 g of methyl isobutyl ketone, and 10 g of water, which were stirred at room temperature. At the end of stirring, the reaction solution was concentrated, followed by twice of azeotropic dehydration with 30 g of methyl isobutyl ketone. To the solid precipitate, 30 g of acetonitrile was added, whereupon solid-liquid washing was conducted for 30 minutes. The solid was filtered and dried, obtaining the target compound, sodium 2,4,6-tricyclohexylbenzoate as white crystal. Amount 2.0 g, yield 90%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[C:16]([OH:18])=O)=[N:7][C:6]=2[CH:19]=1.[CH3:21][C@H:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([CH3:28])[N:23]1[CH2:29][CH2:30][NH2:31]>>[CH3:21][C@H:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([CH3:28])[N:23]1[CH2:29][CH2:30][NH:31][C:16]([C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:10]1[C:8]1[O:9][C:5]2[CH:4]=[C:3]([CH3:20])[C:2]([CH3:1])=[CH:19][C:6]=2[N:7]=1)=[O:18].[NH3:7]
Reactant: Cc1cc2nc(N3CCCC[C@H]3C(=O)O)oc2cc1C
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Product: Cc1cc2nc(N3CCCC[C@H]3C(=O)NCCN3[C@H](C)CCC[C@@H]3C)oc2cc1C
Product: N

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-[5,6-dimethyl-1,3-benzoxazol-2-yl]-2-piperidinecarboxylic acid [see Preparation 53] and 2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamine [J.Med.Chem., 27(5), (1984), 684-691]. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of 93:7:1, by volume, dichloromethane: methanol:0.88 aqueous ammonia solution to afford (2S)-N-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-[1-(5,6-dimethyl-1,3-benzoxazol-2-yl]-2-piperidinecarboxamide as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[CH:9][CH:10]=[O:11].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:27][C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:21]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>C(#N)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:29]=[C:28]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:27][C:22]3([CH2:23][CH2:24][CH2:25][CH2:26]3)[C:21]=2/[CH:8]=[CH:9]/[CH:10]=[O:11])=[CH:16][CH:15]=1
Reactant: CN(C)C=CC=O
Reactant: Fc1ccc(C2=CC3(CCCC3)CC(c3ccc(F)cc3)=C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C/C=C/C1=C(c2ccc(F)cc2)C=C(c2ccc(F)cc2)CC12CCCC2
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a solution of phosphorus oxychloride (1.69 ml, 18.15 mmoles) in 50 ml of acetonitrile cooled in an ice bath was added 3-dimethylaminoacrolein (1.68 ml, 16.75 mmoles) dropwise over 3 minutes. The mixture was stirred for 5 minutes and a solution of 7,9-di-(4-fluorophenyl)spiro[4.5]deca-6,8-diene (4.5 g, 13.96 mmoles) in 150 ml of warm acetonitrile was added dropwise over 30 minutes. The mixture was stirred at room temperature for 16 hours and was then heated in an oil bath at 60° C. for 6 hours. The mixture was cooled and poured into 400 ml of cold 1N sodium hydroxide. The mixture was extracted with ether. The ether was washed with water and evaporated in vacuo. The residue was triturated with 17.5 ml of boiling hexane and was filtered. The filtrate, upon cooling in the freezer overnight, deposited 2.7 g of product having an m.p. of 120°-4° C.