Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.C(OCC)C>[CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([Cl:13])=[O:6]
Reactant: C[Si](C)(C)CCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCC(=O)Cl
Reaction time: 16 h
Yield: 68.9 %

Procedure:
In a flask were place 13.4 g (0.0918 mole) of 4,4-dimethyl-4-silapentanoic acid, 100 mL of diethyl ether, and two drops of N,N-dimethylformamide. To this solution, which was cooled in an ice/water bath, was added 13.98 g (0.110 mole) of oxalyl chloride in diethyl ether in a dropwise manner. Upon completion of addition, the temperature was allowed to rise to ambient conditions, and the mixture was stirred for approximately 16 hours. At the conclusion of this period the solvent was evaporated from the reaction mixture under reduced pressure, leaving 10.42 g of 4,4-dimethyl-4-silapentanoic acid chloride as a residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21]=[C:20](SC)[N:19]=3)=[CH:13][C:12]=2[F:31])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]>C(O)C.[Ni].O>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21]=[CH:20][N:19]=3)=[CH:13][C:12]=2[F:31])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc(Oc2ccnc(C(N)=O)c2)c(F)c1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cncnc1Nc1ccc(Oc2ccnc(C(N)=O)c2)c(F)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of ethyl 4-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-2-(methylthio)pyrimidine-5-carboxylate (260 mg, 0.58 mmol) in ethanol (5 mL) was added Raney nickel in water (Raney®2400, approx. 3 g). The mixture was heated to 70° C. and was allowed to stir overnight. The mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give the desired product (91 mg, 39%) as a solid. MS(ESI+) m/z 398 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([CH2:16][C:17]([O:19]CC)=O)[NH:15][C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[N:30]>>[NH2:30][C:29]1[C:24]2[C:23](=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:22][C:17](=[O:19])[C:16]=1[C:14]1[NH:13][C:11]2=[N:12][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:8][CH:9]=[C:10]2[N:15]=1
Reactant: CCOC(=O)Cc1nc2nc(N3CCOCC3)ccc2[nH]1
Reactant: N#Cc1ccccc1N
Product: Nc1c(-c2nc3ccc(N4CCOCC4)nc3[nH]2)c(=O)[nH]c2ccccc12

Procedure:
The title compound was synthesized as described in Example 45, Method E using ethyl 2-(5-morpholin-4-ylimidazolo[5,4-b]pyridin-2-yl)acetate and 2-aminobenzenecarbonitrile, with a modified workup procedure. After quenching with a saturated aqueous ammonium chloride solution, the two phases were separated and the aqueous phase extracted with EtOAc. Upon standing, a solid formed and precipitated out of the organic extracts. The precipitate, a dark brown solid, was filtered off and dried. Purification by reverse phase chromatography afforded the desired product as a reddish solid. LC/MS m/z 363.2 (MH+), Rt 2.20 minutes.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH3:11].[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[CH3:11][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:22]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:24])=[O:23]
Reactant: Cc1c(C(F)(F)F)noc1N
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: Cc1c(C(F)(F)F)noc1NS(=O)(=O)c1cccc2ccccc12
Yield: 85 %

Procedure:
N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-1-naphthalenesulfonamide was prepared, as described in Example 90, from 5-amino-4-methyl-3-trifluoromethylisoxazole and 1-naphthalenesulfonyl chloride in 85% yield. Purification was achieved by recrystallization from methanol/water to give white needed, m.p. 154°-155° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]1([CH:14]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC1C=CC=CC=1>O>[C:5]([N:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:24]([CH2:23][CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][N:15]([CH:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:16][CH2:17]2)[C:25]1=[O:33])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 1.55 parts of acetic acid anhydride, 3 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and 22.5 parts of methylbenzene is stirred and refluxed overnight. Water is added to the reaction mixture and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-acetyl-3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 124.4° C.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.Cl.Cl[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([O:23][CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: CN(C)CCCCl
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(O)cccc32)cc1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCCCN(C)C)cccc32)cc1
Yield: 63.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and 3-chloro-N,N-dimethylpropylamine hydrochloride (0.32 g) as starting materials, N-[(4-dimethylaminophenyl)-methyl]-5-[3-(dimethylamino)propoxy]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) was obtained. Oxalic acid was added to this compound. By recrystallization from isopropyl alcohol, N-[(4-dimethylaminophenyl)methyl]-5-[3-(dimethylamino)propoxy]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide oxalate ⅘ hydrate (0.18 g) was obtained.
Reaction SMILES: [C:1]1([CH:7]2[S:18][CH:10]3[S:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:9]3[C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[S:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]=[C:10]1[S:18][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19]
Reactant: O=C1C(c2ccccc2)SC2Sc3ccccc3N12
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CCCN1C(=O)C(Sc1nc2ccccc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
5.7 g (0.02 m) 2-phenylthiazolo[2,3-b]benzothiazol-3(2H)-one mesoionic didehydro derivative, 2.2 g (0.02 m)-L-(-)-proline and 2.0 g (0.02 m) triethylamine are suspended in methylene chloride and the mixture is stirred at room temperature overnight. The reaction mixture is extracted with a dilute hydrochloric acid solution and dried over anhydrous magnesium sulfate. After the solvent is removed, the residue is extracted with hot cyclohexane. The solid obtained from the cyclohexane solution is recrystallized from acetonitrile. In order to remove all traces of acetonitrile, the solid is ground, stirred in water for 3 days, collected and then dried in an oven at 90° C. There is thereby obtained 3.0 g (37% yield) of the title compound, which has a melting point of 174°-5° C. (dec).
Reaction SMILES: [Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([O:18][C@H:19]3[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31]([OH:33])=[O:32])[CH2:20]3)[N:6]=[C:7]3[C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:3]=1.[ClH:34].[CH3:35][CH2:36]O>>[ClH:34].[Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([O:18][C@H:19]3[CH2:23][NH:22][C@H:21]([C:31]([O:33][CH2:35][CH3:36])=[O:32])[CH2:20]3)[N:6]=[C:7]3[C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:3]=1
Reactant: CCO
Reactant: COc1cc2c3c(nc(O[C@@H]4C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C4)c2cc1Br)CCCC3
Agent: Cl
Product: CCOC(=O)[C@@H]1C[C@@H](Oc2nc3c(c4cc(OC)c(Br)cc24)CCCC3)CN1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the product from Step 1, (4R)-4-[(8-bromo-9-methoxy-1,2,3,4-tetrahydrophenanthridin-6-yl)oxy]-1-(tert-butoxycarbonyl)-L-proline (500 mg, 0.96 mmol) in EtOH (80 mL) was bubbled HCl (g) for 30 min. The mixture was then stirred for 2 days at r.t. and then the solvent was removed in vacuo to yield the title compound. LRMS (M+H)+=448.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[C:7]([Br:24])[CH:6]=1.CCCCCCC.C(OCC)(=O)C.[N+:39]([O-])([OH:41])=[O:40]>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:14]=[C:15]([CH:21]([CH3:23])[CH3:22])[C:16]([O:19][CH3:20])=[C:17]([N+:39]([O-:41])=[O:40])[CH:18]=2)=[C:7]([Br:24])[CH:6]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)c(C(C)C)c2)c(Br)c1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: COC(=O)Cc1cc(Br)c(Oc2cc(C(C)C)c(OC)c([N+](=O)[O-])c2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of methyl[3,5-dibromo-4-(3-isopropyl-4-methoxyphenoxy)phenyl]acetate (1.0 g, 2.12 mmol) in benzene (150 mL), nitric acid (0.81 mL, 65%) was added drop-wise. The mixture was further stirred for 1 hour at room temperature. The reaction was monitored by TLC (65:35 n-heptane/ethyl acetate) and the reaction mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate. The resulting organic and aqueous phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, brine, and the organic phase was dried over magnesium sulfate, and concentrated. The crude product was crystallized from methanol to give 1.1 g, (99%) of methyl[3,5-dibromo-4-(5-isopropyl-4-methoxy-3-nitrophenoxy)phenyl]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:10]2)=[CH:5][CH:4]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1
Reactant: COc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CN(CCCCN)CC2
Yield: 62.5 %

Procedure:
A solution of 7-methoxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (17.4 g 0.0478 mol) and hydrazine monohydrate (4.6 ml, 0.095 mol) in ethanol (300 ml) were stirred at room temperature for 18 h and at reflux for 1 h. The cooled reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in 2.5N hydrochloric acid, filtered through Kieselguhr and the filtrate basified with 0.880 ammonia. The product was extracted into dichloromethanc (4×200 ml), the combined extracts were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a brown oil (7 g, 63%).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:15])=O.[Cl-].[Al+3].[Cl-].[Cl-].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>ClCCl>[N+:1]([C:4]1[O:8][C:7]([C:9]([Cl:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:1]([C:4]1[O:8][C:7]([C:9]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:22][CH:23]=2)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cl)c1ccc([N+](=O)[O-])o1
Product: O=C(c1ccc([N+](=O)[O-])o1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-nitro-2-furoyl chloride, which was prepared with 5-nitro-2-furoic acid (2.0 g) and oxalyl chloride (1.4 ml) in an usual manner, in dichloromethane (10 ml) was added to a suspension at aluminum chloride (1.78 g) at 25° C. The mixture was stirred at 25° C. for 30 minutes, and then a solution of indole (1.49 g) in dichloromethane (15 ml) was added at 25° C. The mixture was stirred at 25° C. for 1 hour, and poured into ice water. The precipitates were filtered and washed with water, ethyl acetate and hot ethanol to give 3-(5-nitro-2-furoyl)indole (1.08 g) as yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:17][C:18]2[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]=2[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5](C)[CH:4]=1)#[N:2].[Cl:37]C1C=C(C=CC=1C=O)C#N>>[Cl:37][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[N:9]([CH2:17][C:18]1[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(C#N)ccc1N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(C=O)c(Cl)c1
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)c1ccc(C#N)cc1Cl

Procedure:
The title compound is prepared in analogy to tert-butyl (4-cyano-2-methylphenyl)(6-oxo-2-(3-(trifluoromethyl)phenylamino)cyclohex-1-enyl)methylcarbamate (intermediate 51), using 3-chloro-4-formylbenzonitrile (500 mg, 6.04 mmol) as starting material. Yield: 1.05 g; ESI mass spectrum [M+H]+=520; Retention time HPLC: 0.81 min (X012_S01).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17](=[N:20][C:21]#[N:22])SC)=[CH:13][CH:14]=2)[N:9]=1)[NH2:3].[CH2:23]([CH2:25][NH2:26])[OH:24]>CN(C)C=O>[C:21]([N:20]=[C:17]([NH:26][CH2:25][CH2:23][OH:24])[NH:16][CH2:15][C:12]1[O:11][C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)=[CH:14][CH:13]=1)#[N:22]
Reactant: CSC(=NC#N)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Reactant: NCCO
Solvent: CN(C)C=O
Product: N#CN=C(NCCO)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[5-(3-cyano-2-methyl-1-isothioureido)methylfuran-2-yl]thiazole (1.10 g) and monoethanolamine (1 ml) in N,N-dimethylformamide (10 ml) was stirred at 70° C. for 7 hours. The solvent was evaporated in vacuo and the residue was mixed with water. The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of dioxane, methanol and diisopropyl ether to afford 4-[5-{2-cyano-3-(2-hydroxyethyl)guanidino}methylfuran-2-yl]-2-(diaminomethyleneamino)thiazole (0.80 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.Cl.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=2)=[CH:22][CH:21]=1)=[O:18]>ClCCl.CN(C)C=O.C(OCC)(=O)C>[F:35][C:33]([F:34])([F:36])[C:30]1[CH:31]=[CH:32][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:17]([N:1]3[CH2:2][CH2:3][CH:4]([CH2:7][N:8]4[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]4)[CH2:5][CH2:6]3)=[O:18])=[CH:21][CH:22]=2)=[N:28][CH:29]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: OC1CCN(CC2CCNCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(CN2CCC(O)CC2)CC1

Procedure:
The title product was prepared from 1-piperidin-4-ylmethyl-piperidine-4-ol (released form the correspondent hydrochloride by a standard procedure) and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (reaction performed in a mixture of dichloromethane and dimethylformamide). 1.7 M HCl in ethyl acetate was added to the pooled fractions containing the title product, and the fractions was evaporated to dryness (92%, white solid. HPLC-MS m/z=(M+1) 480.4, Rt: 2.38 min.
Reaction SMILES: C1(N(C2C=CC=CC=2)[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])C=CC=CC=1.C(O)(=[O:26])C.S(=O)(=O)(O)O>O>[CH:10]([C:8]([OH:9])=[O:26])=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)O
Reactant: O=C(C=Cc1ccccc1)N(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C=Cc1ccccc1
Temperature: 25 °C

Procedure:
The N,N-diphenylstyrenyl carboxamide-2% divinylbenzene copolymer from example 7(a) (53.0g) was heated with stirring at 130°-135° for 44 hours with a mixture of glacial acetic acid (670 ml.), concentrated sulphuric acid (500 ml.) and water (300 ml.). After cooling to room temperature, the mixture was filtered and the polymer washed successively with water (4 × 400 ml.), acetone (3 × 200 ml.); methanol (3 × 200ml.), water (2 × 400 ml.) and acetone (2 × 200 ml.); and dried in vacuo at 40° to constant weight. The title polymer (36.58g) was green in colour and exhibited ν max (NuJol) 1690 (C=O) and 3700-2400 (OH) cm-1. Titration was effected by suspending the product (0.500g) in 95% ethanol (50 ml.) adding 0.5M sodium hydroxide (50 ml.), warming the mixture to reflux, cooling and back titrating with 0.5M hydrochloric acid using phenolphthalein as the indicator; it was found that 47.12 ml. of acid were required for neutralisation indicating 2.88 m.mole carboxyl/g of polymer.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:32]3[CH:27]=[CH:28][CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[N:31]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccc(I)cn1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1cccc(C(F)(F)F)n1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 239 mg (0.66 mmol) of 75% 5-iodo-2-trifluoromethyl-pyridine in 1 mL THF with 0.37 mL 2M isopropylmagnesium chloride. Yield: 78 mg of a white powder. LC-MSD, m/z for C22H13BrF3N3O2 [M+H]+=488.0, 490.0; HPLC retention time: 2.4 min.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.CCO.[Cl-].[NH4+]>C1COCC1.[Fe]>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: N#Cc1ccc([N+](=O)[O-])c2cccnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(N)c2cccnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Compound 464B (6.00 g, 30.1 mmol) was dissolved in THF (150 mL) at reflux with mechanical stirring. EtOH (150 mL) was then added followed by aqueous ammonium chloride (2.4 g/225 mL water). The mixture was heated at 70° C. and then iron powder (325 mesh, 6.75 g, 120 mmol) was added with vigorous mechanical stirring. After 1 h, the reaction was cooled to 22° C. and filtered through Celite rinsing with methylene chloride. The filtrate was then concentrated to ˜250 mL and the pH was adjusted to 10 by addition of 1N NaOH. The solution was then extracted with ethyl acetate (5×150 mL). The combined organic layers were washed once with brine (250 mL) and then dried over anhydrous magnesium sulfate. Concentration in vacuo gave 5.09 g (100%) of compound 464C as a yellow solid. HPLC: 99% at 1.143 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 170.16 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:14]=[C:13]1[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:15])[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 16 h
Yield: 93.8 %

Procedure:
6-amino hexanoic acid 39a (13.1 g, 100 mmol) and phthalic anhydride (40) (14.8 g, 100 mmol) were mixed in toluene (150 mL). To the suspension was added triethyl amine (13 mL). The suspension was refluxed using Dean-stark for 16 h. When collection of water ceased, the reaction was cooled and evaporated to dryness. The residue was suspended in water and conc. hydrochloric acid (1.5 mL) was added. The suspension was stirred for 30 mins and filtered. The precipitate was washed with water and dried over sodium sulfate to afford compound 41a (24.5 g, 93%) which was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.C(O[BH-](O[C:47](=O)[CH3:48])OC(=O)C)(=O)C.[Na+].[C:51](=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH:47]([CH3:48])[CH3:51])[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(C(C)C)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.095 mmol) in dichloromethane (1 mL) was added under an atmosphere of nitrogen acetone (70 μl, 0.95 mmol) and sodium triacetoxyborohydride (81 mg, 0.38 mmol). The reaction mixture was stirred for 18 h at ambient temperature before it was treated with an aqueous solution of sodium carbonate (1 M, 10 ml) and stirred for 1 h at this temperature. It was diluted with ethyl acetate (15 mL). The aqueous layer was extracted with ethyl acetate (15 mL) and the organic layers were washed with brine (15 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 70:30) afforded the title compound (40 mg, 73%) as a light brown oil. MS m/e: 566.3 [M]+.