Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13]>>[CH3:9][O:10][C:11](=[O:14])[C@H:12]([CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8])[NH2:13]
Reactant: COC(=O)CN
Reactant: O=Cc1ccccc1
Product: COC(=O)[C@@H](N)C(O)c1ccccc1

Procedure:
European Patent Application No. 0 220 923, published May 6, 1987, corresponding to commonly assigned copending U.S. Patent application Ser. No. 789,595, filed Oct. 21, 1985, describes the use of SHMT obtained from a genetically engineered Escherichia coli strain transformed with the pGS29 plasmid for condensing benzaldehyde and glycine methyl ester to produce betaphenylserine methyl ester. The reaction conditions employed during the condensation reaction include a pH of from 6.5 to 9, a temperature of from 10 to 65° C., a benzaldehyde concentration of from 10 to 100 mM and a glycine ester from 10 to 150 mM. While at a betaphenylserine methyl ester yield of 1.48 g/l, this process produced a beta-phenylserine methyl ester product containing as much as 83% erythro isomer, it has been found that as the yield is increased the amount of threo isomer present in the product increases until at commercial rates of production substantial amounts of threo isomer are present.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[CH3:17][NH2:18].O>C(Cl)(Cl)Cl>[CH3:17][NH:18][CH:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CN
Reactant: CC(Br)C(=O)c1ccc(OCC(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNC(C)C(=O)c1ccc(OCC(=O)O)cc1
Reaction time: 1.5 h
Yield: 65 %

Procedure:
4-(2-bromopropionyl)phenoxyacetic acid (5 g, 17.5 mmol) in chloroform (50 ml) was stirred vigorously at 35-40° C. and a solution of 40% methylamine in water (4.05 ml, 52 mmol) was added dropwise over 30 mins. Stirring was continued at this temperature for a further 1.5 h after addition. The mixture was evaporated to dryness and the crude residue was purified by column chromatography (silica gel: 10% methanol in chloroform) to give the title product (2.7 g, 65%) as a white foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=[C:4]2[N:3]=1.CN(C)C=O.[CH:23]([NH:26][CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24]>>[CH:23]([N:26]([CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=[C:4]2[N:3]=1)([CH3:25])[CH3:24]
Reactant: CC(C)NC(C)C
Reactant: Cc1cc(Cl)nc2nc(N3CCOCC3)nn12
Solvent: CN(C)C=O
Product: Cc1cc(N(C(C)C)C(C)C)nc2nc(N3CCOCC3)nn12
Reaction time: 24 h

Procedure:
To a solution of 2.54 g (0.01 mole) of 5-chloro-7-methyl-2-morpholino-1,2,4-triazolo[1,5-a]pyrimidine in 10 ml of dimethylformamide 2.02 g (0.02 mole≈2.8 ml) of diisopropylamine are added, and the reaction mixture is boiled for 24 hours under stirring. The solution thus obtained is evaporated to dryness in vacuo and the residue is recrystallized from 20 ml of water.
Reaction SMILES: C([NH:18][CH:19]([C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:22]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:21]=1[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(NCC)C>C(Cl)(Cl)Cl.C(#N)C>[C:83]1([CH:19]([NH2:18])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:22]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:21]=2[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(NC(=O)OCC2c3ccccc3-c3ccccc32)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Solvent: CC#N
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(N)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reaction time: 5 h
Yield: 101.8 %

Procedure:
N-Fmoc-[phenyl(2,3,4-trioctadecanoxyphenyl)methyl]amine (830 mg, 684 μmol) obtained in Example 2 was dissolved in chloroform (10 ml) and acetonitrile (6 ml), diethylamine (2.04 ml, 1.97 mmol) was added dropwise, and the mixture was stirred for 5 hours. The solvent was evaporated, and the residue was washed with acetonitrile (10 ml) to give [phenyl(2,3,4-trioctadecanoxyphenyl)methyl]amine (668 mg, 696 μmol, yield 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[NH:31][C:32]([O:34]C1C=CC=CC=1)=O)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:14])[CH:7]=1.[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CN(C)C=O>O>[NH:41]([C:32]([NH:31][C:30]1[CH:29]=[CH:28][C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:19][CH2:20]3)=[O:14])[CH:7]=2)=[CH:3][C:2]=1[Cl:1])=[O:34])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccn2)CC1
Reactant: Nc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Yield: 48.1 %

Procedure:
t-Butyl 4-{[(4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-2-pyridyl)amino]carbonyl}-1-piperidine carboxylate (250 mg), aniline (84 mg) and dimethylformamide (3 ml) were stirred at 130° C. for 70 minutes. The mixture was returned to room temperature, water was added and extraction was performed with ethyl acetate. Silica gel was added to the extract, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with silica gel, and column purification was performed (hexane:ethyl acetate=1:1, followed by ethyl acetate). The solvent was distilled off under reduced pressure to obtain 120 mg of a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]3[CH2:13][CH:8]([C:9]=2[CH:10]=[CH:11][CH:12]=1)[CH2:7][N:6](C(=O)C(F)(F)F)[CH2:5]3.[Cl:20][C:21]1[CH:30]=[CH:29]C2C(=CC=CC=2)[N:22]=1>>[ClH:20].[Cl:20][C:21]1[CH:30]=[CH:29][C:12]2[C:11](=[CH:10][C:9]3[CH:8]4[CH2:13][CH:4]([C:3]=3[C:2]=2[F:1])[CH2:5][NH:6][CH2:7]4)[N:22]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C(N1CC2CC(C1)c1c(F)cccc12)C(F)(F)F
Product: Cl
Product: Fc1c2c(cc3nc(Cl)ccc13)C1CNCC2C1

Procedure:
1-(6-Chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone 3-Fluoro-10-aza-tricyclo[6.3.1.02,7]-dodeca-2(7),3,5-triene was converted to 1-(3-Fluoro-10-aza-tricyclo[6.3.1.02,7]-dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone by the methods described in Example 7A. This product was nitrated as described in Example 7B. The resulting mixture of nitrated products was reduced as described in Example 8, then converted to a chloroquinoline as described in Examples 54 and 55. These products were separated by column chromatography on silica gel to provide the title compound. (TLC: 50% ethyl acetate/hexanes, Rf 0.50).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH:15][CH3:16])[N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:25])[CH2:19]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>CC#N.O>[CH3:16][NH:15][C:4]1[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:7]=[C:2]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:35])([F:36])[F:37])=[O:25])[CH2:19]2)[N:3]=1
Reactant: NC1CCCC(C(=O)NCc2ccccc2C(F)(F)F)C1
Reactant: CNc1nc(Cl)nc(N2CCN(C)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(NC2CCCC(C(=O)NCc3ccccc3C(F)(F)F)C2)nc(N2CCN(C)CC2)n1
Temperature: 80 °C
Yield: 1.8 %

Procedure:
The solution of 4-chloro-N-methyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (30.0 mg, 0.084 mmol, 1 equivalent) and 3-amino-N-(2-(trifluoromethyl)benzyl) cyclohexanecarboxamide as TFA salt (103 mg, 0.248 mmol, 2.95 equivalents) in CH3CN/H2O (1/1, 2 ml) was adjusted to pH 9-10 with 1N NaOH. The resulting solution was heated at 80° C. for 16 hours. The solvent was removed under vacuo to give the crude product, which was purified with RP-HPLC (Luna 5μ, C8(2), 100×21 mm, 10-50% CH3CN/H2O, 0.1% TFA, 25 min) to give the final compound (0.94 mg, 1.8%). MS (ES+): m/e 507.17 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.[C@@H:20]1([NH2:30])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>>[C@@H:20]1([NH:30][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:5]3[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=3)[CH:8]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Oc2cccc(C(F)(F)F)c2)c1
Product: FC(F)(F)c1cccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)c1

Procedure:
3-[3-(Trifluoromethyl)phenoxy]benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([CH2:27][OH:28])[O:18]1>>[CH3:15][O:16][C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([CH2:27][O:28][C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=2[C:6]#[N:7])[O:18]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CO[C@@H]1O[C@H](CO)[C@H]2OC(C)(C)O[C@@H]12
Product: CO[C@@H]1O[C@H](COc2cccc([N+](=O)[O-])c2C#N)[C@H]2OC(C)(C)O[C@@H]12
Yield: 70 %

Procedure:
Prepared as in Example 158c from 2,6 dinitrobenzonitrile and ((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol in 70% yield as white solid. 1H NMR (400 MHz, CDCl3) δ 1.33 (s, 3H), 1.49 (s, 3H), 3.32 (s, 3H), 4.23 (d, J=2.0 Hz, 1H), 4.24 (s, 1H), 4.60 (br t, J=6.0 Hz, 1H), 4.67 (d, J=6.0 Hz, 1H), 4.86 (br d, J=6.0 Hz, 1H), 5.01 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.72 (t, J=8.4 Hz, 1H), 7.87 (dd, J=0.8, 8.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][N:5]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([NH2:12])[C:6]1=[O:13].[C:15]1([C:25]([OH:27])=O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.ON1C2C=CC=C[C:32]=2N=N1>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH2:1]([O:2][C:3](=[O:14])[CH2:4][N:5]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([NH:12][C:25]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[O:27])[C:6]1=[O:13])[CH3:32]
Reactant: COC(=O)CN1CC=CCC(N)C1=O
Reactant: O=C(O)c1nccc2ccccc12
Reactant: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(3-amino-2-oxo-2,3,4,7-tetrahydroazepin-1-yl) acetic acid methyl ester, 3, (0.365 g, 1.68 mmol) is dissolved in 1:1 CH2Cl2/DMF and 1-isoquinoline-carboxylic acid (1.4 g, 8.1 mmol), 1-hydroxybenzotriazole (0.35 g, 2.6 mmol), and 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (0.5 g, 2.6 mmol) are added. The resulting solution is stirred at room temperature for 12 hours, diluted with EtOAc, washed with saturated NaHCO3 then brine, and dried (MgSO4). The solvent is removed in vacuo and the resulting residue is purified over silica gel (EtOAc/hexane) to afford the desired product.
Reaction SMILES: N[CH:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](Cl)=[O:13].CC[N:17](C(C)C)C(C)C>>[CH3:10][O:11][C:12](=[O:13])[NH:17][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)Cl
Reactant: NC(O)c1ccccc1
Product: COC(=O)Nc1ccccc1CO

Procedure:
Reaction of aminobenzylalcohol (3 g) with methylchloroformate (1.9 ml) in the presence of DIPEA (12.8 ml) was performed according to the method described in example 22. The residue was chromatographed on silica gel in dichloromethane/ethyl acetate=25/1 as eluent. Yield: 4.19 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:30]B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH3:30])=[CH:10][CH:9]=2)=[O:4]
Reactant: CB(O)O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(C)ccc2c(=O)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), methylboronic acid (200 mg), tetrakis(triphenylphosphine)palladium(0) (80 mg), potassium carbonate (280 mg), toluene (6 ml) and THF (3 ml) was stirred at 100° C. under a nitrogen atmosphere for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and the residue was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (210 mg).
Reaction SMILES: [CH2:1](C1C(=O)C2C=CSC=2CC1)CC.[C:14]1(=[O:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1.C(I)C>>[CH2:15]([CH:16]1[CH2:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]1=[O:24])[CH3:1]
Reactant: CCCC1CCc2sccc2C1=O
Reactant: O=C1CCCc2ccccc21
Solvent: CCI
Product: CCC1Cc2ccccc2C1=O

Procedure:
Following the procedure for the preparation of 5-propyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting 1-tetralone and ethyl iodide, and making non-critical variations provided the title compound as a colorless mobile oil. IR (liq.) 2963, 2933, 2875, 2860, 1712, 1610, 1588, 1475, 1464, 1327, 1296, 1278, 1205, 749, 718 cm−1; MS (EI) m/z 160 (M+); Anal. Calcd for C11H12O: C, 82.46; H, 7.55. Found: C, 82.16; H, 7.57.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Cl:30])[C:9]=2[C:8]1=[O:20]
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1Cl
Product: O=C1c2c(-c3ccccc3Cl)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 87.2 %

Procedure:
In a similar manner to Reference Example 4, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (300 mg) was reacted with 2-chlorophenylboronic acid (133 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (254 mg, 87%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]OC2C=CC=CC=2)[CH:2]=1.[ClH:15].[CH3:16][OH:17]>O=[Pt]=O>[ClH:15].[CH3:16][O:17][C:3]1[CH:2]=[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: c1ccc(OCc2cccnc2)cc1
Agent: O=[Pt]=O
Agent: Cl
Product: COc1cccc(C2CCCNC2)c1

Procedure:
To a solution of 3-(3-pyridinyl)methoxybenzene (22.0 g, 0.099 mol) in methanol (250 ml), PtO2 (2 g) and conc. HCl (30 ml) were added and the mixture was hydrogenated at 0.34 MPa in a Parr apparatus. After complete hydrogenation, the catalyst was filtered off Most of the solvent was evaporated, the residue was made alkaline with 1M NaOH and extracted with ether. The ether-phase was dried (Na2SO4) and the solvent evaporated giving 18 g of the amine product. The hydrochloride was made and then recrystallized from ethanol/ether yielding 20.9 g (93%), mp. 137-138.5° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@H:3]1[OH:15].Cl[C:17]1[C:18]2[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH2:8]([N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:17]2[C:18]3[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[C@H:3]([OH:15])[CH2:4]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Reactant: FC(F)(F)Cc1cc2c(Cl)ncnc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O[C@@H]1CN(Cc2ccccc2)CC[C@H]1Nc1ncnc2sc(CC(F)(F)F)cc12

Procedure:
The mixture of 36.7 mg of trans-4-amino-1-benzylpiperidin-3-ol (0.18 mmol), 30 mg of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (0.12 mmol) and 46 mg of N,N-diisopropylethylamine (0.36 mmol) was refluxed in 0.75 mL of isopropanol for 18 hs. Then reaction mixture was concentrated and purified on silica gel column eluting with DCM:MeOH 20:1 to afford 45 mf of trans-1-benzyl-4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-3-ol (Compound 165). Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. 1H NMR (600 MHz, CD3OD) of HCl salt, signals are all broadened because of intramolecular H-bond: δ 8.37 (1H), 7.51-7.60 (6H), 4.43 (4H), 4.12 (1H), 3.85 (2H), 3.55 (2H), 3.21 (1H), 2.99 (1H), 2.06 (1H). 13C NMR (150 MHz, CD3OD): δC 165.78, 158.45, 153.97, 132.59, 131.46, 130.51, 130.18, 127.45, 125.62, 122.09, 118.50, 68.02, 61.86, 56.88, 54.15, 52.38, 35.81 (q, J=31.5 Hz), 28.14. ESI MS [MH+]: 423.1458.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:7].CO.C1COCC1>O>[CH:10]1[C:11]2[NH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=1
Reactant: COC(=O)c1ccc2[nH]c3ccccc3c2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2[nH]c3ccccc3c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A mixture of dicylcohexylphosphino-2′,3′-dimethoxy biphenyl (17 mg, 0.04 mmol), palladium(II) acetate (5 mg, 0.02 mmol) in toluene (20 mL) was degassed with argon gas for 15 min. To the resulting mixture was added aniline (136 mg, 1.4 mmol), K3PO4 (636 mg, 3.0 mmol), and 4-bromobenzoic acid methyl ester (300 mg, 1.4 mmol) and stirring was continued at reflux temperature overnight. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 15% ethyl acetate in hexane as eluent) to afford 200 mg (63.4% Yield) of 4-phenylamino-benzoic acid methyl ester. A stirred solution of 4-phenylamino-benzoic acid methyl ester (98 mg, 0.43 mmol), Palladium acetate (193 mg, 0.86 mmol) in acetic acid (2 mL) was heated at 110° C. for 15 hr. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate and washed with sodium bicarbonate solution. The organic layer collected was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 10% ethyl acetate in hexane as eluent) to afford 120 mg (60.3% Yield) of 9H-carbazole-3-carboxylic acid methyl ester. LiOH.H2O (680 mg, 16.2 mmol) was added to a stirred solution of 9H-carbazole-3-carboxylic acid methyl ester (120 mg, 0.53 mmol) in the mixture of methanol (1 mL), THF (3 mL) and H2O (1 mL). The reaction mixture was stirred at 60° C. for 3 hrs. The reaction mixture was concentrated. The residue was diluted with water, acidified with aqueous 10% aqueous HCl solution, filtered the solid to afford 104 mg (92.85% Yields) of 9H-carbazole-3-carboxylic acid.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23](Cl)[CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:17][CH:16]=1>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)=[CH:17][CH:16]=1
Reactant: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
11 mg of a 55% w/w suspension of sodium hydride in mineral oil were added, whilst ice-cooling, to a solution of 40 mg of methyl 4-mercaptobenzoate in 0.25 ml of dry dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 52 mg of 1-[4-(4-chlorophenyl)-2-chlorobutyl]imidazole in 0.25 ml of dry dimethylformamide was added to this solution, and the resulting mixture was heated at 60°-70° C. for 5 hours. At the end of this time, the reaction mixture was treated and purified according to the same method as described in Example 1, to give 34 mg of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:20][CH3:21])=[C:8]([CH:10]2[C:16](=[O:17])[CH:15]3[CH2:18][CH:12]([CH2:13][CH2:14]3)[C:11]2=[O:19])[CH:9]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[CH3:38][O:37][C:35](=[O:36])[O:17][C:16]1[CH:15]2[CH2:18][CH:12]([C:11](=[O:19])[C:10]=1[C:8]1[CH:9]=[C:4]([C:3]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=3[Cl:1])[CH:5]=[CH:6][C:7]=1[CH2:20][CH3:21])[CH2:13][CH2:14]2
Reactant: COC(=O)Cl
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C2CCC(C2)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1=C(OC(=O)OC)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(2′,4′-dichloro-4-ethylbiphen-3-yl)-bicyclo[3.2.1]octane-2,4-dione (0.133 g, 0.34 mmol) in dichloromethane (2 ml) is added triethylamine (0.24 ml, 1.72 mmol) followed by stirring at room temperature for 5 minutes. To this solution is added methyl chloroformate (0.132 ml, 1.72 mmol) dropwise, then the mixture is left to stand overnight. The reaction mixture is concentrated in vacuo to afford a crude solid which is purified by flash column chromatography on silica gel (100% to 70% hexane/ethyl acetate eluant ratio) to afford carbonic acid 3-(2′,4′-dichloro-4-ethylbiphen-3-yl)-4-oxo-bicyclo[3.2.1]oct-2-en-2-yl ester methyl ester.