Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:27]1[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:27]3[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1nc(Cl)cc(C#N)n1
Reactant: NCC[C@@H]1C[C@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(C#N)cc(NCC[C@@H]2C[C@H]2C2CCN(c3ncc(Cl)cn3)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine from Example 60 Step 1 (50 mg, 0.178 mmol) was in 0.5 mL DMF. Cs2CO3 (290 mg, 0.890 mmol) was added. Reaction mixture was stirred at room temperature for 10 min before cooled to 0° C. in ice bath. 6-chloro-2-methylpyrimidine-4-carbonitrile from Example 5 step 4 (30.1 mg, 0.196 mmol) in 0.3 mL DMF was added via syringe. Reaction was stirred at 0° C. in ice bath for 2 hours. The mixture was quenched with ice water and aqueous phase was further extracted with ethyl acetate for 3 times. The combined organic layers were washed with water and brine, then dried over Na2SO4 and concentrated. The residue was purified by column chromatography eluting with 30% Ethyl acetate/hexane with 0.5% 2M NH3-MeOH to give the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].[C:31]([O:35][C:36]([NH-:38])=[O:37])([CH3:34])([CH3:33])[CH3:32].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(OCC)(=O)C.C(#N)C>[CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])=[CH:22][CH:23]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC([NH-])=O
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(CNC(=O)OC(C)(C)C)cc2)nc1
Temperature: 25 °C

Procedure:
A mixture of 1-[6-(4-Formyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.1 g, 0.24 mmol), tert-butoxycarbonylamide (0.083 g, 0.71 mmol), triethylsilane (0.11 mL, 0.083 g, 0.71 mmol) and acetonitrile (1 mL) was treated with trifluoroacetic acid (0.035 mL, 0.46 mmol) and stirred for 48 at ambient temperature. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, brine, dried over sodium sulphate, filtered and concentrated in vacuo, affording 1-{6-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-pyridin-3-yl}-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:24][C:25]1[N:29](CCO)[C:28]([N+:33]([O-:35])=[O:34])=[CH:27][N:26]=1>>[CH3:24][C:25]1[NH:29][C:28]([N+:33]([O-:35])=[O:34])=[CH:27][N:26]=1.[CH2:24]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([C:17]([O-:19])=[O:18])=[CH:16][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:25]
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Solvent: O=S(Cl)Cl
Product: CCN1c2ccccc2C(C(=O)[O-])=CC1c1ccccc1
Product: Cc1ncc([N+](=O)[O-])[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
The reaction mixture of 2-Phenyl-4-quinolinecarboxylic acid (249 mg, 1.0 mmol) and thionyl chloride (1.5 ml) was refluxed for 2 h. The excessive thionyl chloride was evaporated undervacuum. The residue was dissolved in 5 ml of pyridine. To this solution, metronidazole (170 mg, 0.98 mmol) was added. The mixture solution was stirred at 80° C. for 2 h. Pyridine was removed under reduced pressure. The residue was dissolved in dichloromethane. The organic layer of CH2Cl2 was washed with saturated aqueous NaHCO3, H2O, and brine, and then dried over MgSO4. The solvent was removed under vacuum. The resulting yellow solid was recrystallized from CH3OH-EtOAc to give 32 mg 2-methyl-5-nitro-1H-imidazole-1-ethyl2-phenyl-4-quinolinecarboxylate. m.p.: 122-124° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][CH:8]=1.[NH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31](=[O:34])[NH:32][N:33]=2)=[CH:24][C:23]=1[CH3:35]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][NH:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31](=[O:34])[NH:32][N:33]=3)=[CH:24][C:23]=2[CH3:35])=[CH:9][CH:8]=1
Reactant: Cc1cc(-c2ccc(=O)[nH]n2)ccc1OCCN
Reactant: COCCOCc1ccc(OCC2CO2)cc1
Product: COCCOCc1ccc(OCC(O)CNCCOc2ccc(-c3ccc(=O)[nH]n3)cc2C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-methoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-3(2H)-pyridazinone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[OH:12].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[NH4+].[OH-].C(Cl)Cl>CO>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[N:21]=[CH:22][C:23]([C:2]3[CH:3]=[C:4]4[C:9](=[N:10][CH:11]=3)[NH:8][CH2:7][CH2:6][CH:5]4[OH:12])=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: OC1CCNc2ncc(Br)cc21
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(O)CCN4)cn2)CC1
Yield: 22 %

Procedure:
6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (89 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (125 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-10% (5% NH4OH in methanol)/methylene chloride as the eluting solvent gave the title compound as brown solids (22% yield). M.p. 124-128° C., LCMS: m/z=326 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00 (m, 1H), 2.08 (s, 1H), 2.62 (t, J=5.0 Hz, 4H), 3.49 (m, 2H), 3.58 (m, 2H), 3.63 (t, J=5.0 Hz, 4H), 4.85 (t, J=4.0 Hz, 1H), 6.68 (s, 1H), 6.71 (s, 1H), 7.59 (dd, J=2.6, 8.8 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 8.32 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[NH:30][C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[C:21]=1[OH:38])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:39]N1C(C)(C)C(=O)N(Cl)C1=O.C(OCC)(=O)C>CC(C)=O>[CH2:1]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:29]=[C:28]([Cl:39])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[NH:30][C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[C:21]=1[OH:38])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCCCNC(=O)c1ccc2c(NC(=O)OCC(C)C)cccc2c1O
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCOCCCNC(=O)c1cc(Cl)c2c(NC(=O)OCC(C)C)cccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
In 30 ml of acetone, 5.28 g (0.01 mol) of 2-(3-dodecoxypropylcarbamoyl)-5-isobutoxycarbonylamino-1-naphthol synthesized in accordance with the method described in JP-A No. 123158/1987 was dissolved and 2.00 g (0.01 mol) of 1,3-dichloro-5,5-dimethylhydantoin was added to the solution, followed by stirring for 2 hours at room temperature. Then 50 ml of ethyl acetate was added to the reaction mixture, followed by washing with a 5% aqueous sodium hydroxide solution and then washing with water. The solvent was distilled off and crystallization from acetonitrile was carried out, to give 5.17 g (yield: 92%) of 2-(3-dodecoxypropylcarbamoyl)-4-chloro-5-isobutoxycarbonylamino-1-naphthol
Reaction SMILES: [C:1](=O)([O-:3])[O-:2].[Na+:5].[Na+].[S:7](=[O:9])=[O:8]>>[S:7]([O-:2])([O-:9])=[O:8].[Na+:5].[Na+:5].[C:1](=[O:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=S=O
Agent: [Na+]
Product: O=C=O
Product: O=S([O-])[O-]

Procedure:
In a brief overview, a source of sodium carbonate (e.g., via line 111) with a source of sulfur dioxide (e.g., via line 112) are fed to the reactor 110 under conditions suitable to produce sodium sulfite with carbon dioxide as a by-product and generate a sodium sulfite liquor which exits reactor 10 via line 114. The reactor 110 is typically operated at a temperature from 120° F. to 140° F. (from 48.9 to 60° C.), or at about 160° F. (about 71° C.).
Reaction SMILES: [C:1]1([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:11][CH2:10][CH2:9][C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:22]([O-])([OH:24])=[O:23].[OH-].[Na+]>C(OC(=O)C)(=O)C>[N+:22]([C:4]1[CH:3]=[CH:2][C:1]([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:11][CH2:10][CH2:9][C:8]2=[O:21])=[CH:6][CH:5]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCCC(c2ccc(Cl)c(Cl)c2)N1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCC(c2ccc(Cl)c(Cl)c2)N1c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
To a solution of 1.0 g of 1-phenyl-6-(3,4-dichlorophenyl)-2-piperidone in 0.5 ml of acetic anhydride was added 1 ml of fuming nitric acid at 0° to 10° C., and the mixture was stirred for 3 hours. The mixture was made alkaline under cooling with an aqueous 10% sodium hydroxide solution and extracted with toluene. After washing with water and drying, the solvent was evaporated. The residue was purified by silica gel column chromatography (solvent; acetone:n-hexane=1:1) to give 0.35 g of 1-(4-nitrophenyl)-6-(3,4-dichlorophenyl)-2-piperidone as colorless foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[C-:12]#[N:13].[Na+].C([O-])(O)=O.[Na+]>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:12]#[N:13])[N:7]=1
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution 2-chloro-4-(trifluoromethyl)pyrimidine (5.00 g, 27.4 mmol) in dimethyl sulfoxide (25 mL) was added sodium cyanide (1.68 g, 34.2 mmol). The reaction was stirred at room temperature for 30 minutes and poured into cold saturated aqueous NaHCO3 solution. The mixture was transferred to a 100 mL separatory funnel and extracted with ethyl ether (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound, 4-trifluoromethyl-pyrimidine-2-carbonitrile, as a brown oil, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ9.16 (d, J=5.1 Hz, 1H), 7.88 (d, J=5.1 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=[C:32]1[CH2:31][CH2:30][CH2:29][CH2:28]C2.BrCC1CCC1.O>C(O)C.C(OCC)(=O)C>[CH:29]1([CH2:28][O:1][C:2]2[CH:3]=[C:4]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]4[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])[N:14]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:30][CH2:31][CH2:32]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Agent: BrCC1CCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OCC1CCC1

Procedure:
A 0.15 g quantity of 3-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained in Example 136 and 0.15 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5 ml of ethanol, 0.13 g of (bromomethyl)cyclobutane was added thereto, and the mixture was heated and refluxed overnight. After standing to cool, water was added to the reaction mixture, and ethyl acetate extraction was performed. The extract was washed twice with water, the organic layer was then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), thereby yielding 90 mg of white powdery 3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: C([C@H]1CC[C@H]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29]CCCCCCC)=[CH:23][CH:22]=3)[CH:18]=[CH:17][C:16]=2O)=[O:13])CC1)CCCC.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41](S(O)(=O)=O)=[CH:40][CH:39]=1.Cl[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1Cl>>[CH2:17]([C@H:50]1[CH2:55][CH2:54][C@H:53]([C:12]2[O:13][C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:48][CH2:38][CH2:43][CH2:42][CH2:41][CH2:40][CH3:39])=[CH:23][CH:22]=4)=[CH:20][C:15]=3[N:14]=2)[CH2:52][CH2:51]1)[CH2:16][CH2:15][CH2:20][CH3:19]
Reactant: CCCCCCCCCCc1ccc(-c2ccc(O)c(NC(=O)[C@H]3CC[C@H](CCCCC)CC3)c2)cc1
Reactant: Clc1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCc1ccc(-c2ccc3oc([C@H]4CC[C@H](CCCCC)CC4)nc3c2)cc1
Reaction time: 0.67 h

Procedure:
Step ii) In a 30 ml-round-bottomed flask, 0.60 g (1.19 mM) of 2-(trans-4-pentylcyclohexylcarbonylamino)-4-(4decylphenyl)phenol, 0.07 g (0.37 mM) of p-toluenesulfonic acid and 10 ml of o-dichlorobenzene were placed, followed by stirring for 40 min. at 188°-192° C. After the reaction, o-dichlorobenzene was distilled-off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 0.28 g of 2-(trans-4-pentylcyclohexyl)-5-(4-decylphenyl)benzoxazole (yield: 48.4%). ##STR100##
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=2)[C:3]1=[O:16].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][C:32]2([F:38])[F:37])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][N:34]([CH:2]3[CH2:6][CH2:5][N:4]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=4)[C:3]3=[O:16])[CH2:33][C:32]2([F:38])[F:37])=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: FC1(F)CNCCC1c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(CN2CCC(N3CCC(c4ccc(OCc5ccccc5)cc4)C(F)(F)C3)C2=O)cc1F
Temperature: 120 °C

Procedure:
To a mixture of 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (0.51 g, 1.8 mmol, Intermediate 6) and 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (0.3 g, 1 mmol, from step C) was added triethylamine (0.69 mL, 4.9 mmol) and the resulting mixture was heated in a sealed tube at 120° C. for 1 h. The reaction mixture was allowed to cool and then diluted with water and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue (0.45 grams, 64%, mixture of 4 diastereoisomers) was used directly in the next step without further purification, LCMS (method P) RT 1.19 min, m/z 509 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[N:18]=[C:17](S(C)(=O)=O)[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:35]#[N:36].[Na+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[N:18]=[C:17]([C:35]#[N:36])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(S(C)(=O)=O)n2)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Yield: 83.7 %

Procedure:
4-[2-Methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (139 mg) and sodium cyanide (22 mg) were heated to 45° C. in dimethylsulphoxide for four hours. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (3×30 ml). Organics were separated, dried over sodium sulphate and solvent was evaporated to yield product 4-[2-cyano-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (104 mg). The above product was then dissolved in dichloromethane (1 ml) and cooled to 0° C. Trifluoroacetic acid (200 μL) was added and the mixture stirred for ten minutes. Solvent was evaporated under reduced pressure to yield crude product. Purification by preparative HPLC yielded product 4-[1,4]diazepan-1-yl-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (52 mg) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:27])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=2)[CH2:10][CH2:9]1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)C>[CH3:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][C:15](=[O:27])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:20]([O:25][CH3:26])[CH:19]=2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)cc1OC
Reaction time: 0.33 h

Procedure:
1.03 g of potassium carbonate was added to a solution of 2.15 g of N-(cis-4-methylcyclohexyl)-4-hydroxy -3-methoxycinnamamide (Example 105) in 200 ml of ethanol. The solution was stirred for 20 minutes, while it was refluxed. Next, 8.0 ml of ethyl bromoacetate was slowly added dropwise to the solution by means of a dropping funnel. Thereafter, the solution was stirred for 4 hours. After reaction, the potassium carbonate was filtered from the reaction solution, and the solvent was removed in vacuo from the filtrate. The product obtained was recrystallized from methylene chloride/ether, yielding 2.12 g of N-(cis-4-methylcyclohexyl) -4-(ethoxycarbonylmethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]2[C:15](=[O:16])[CH2:14][C:13]3[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:12]=3[CH2:11][CH2:10]2)[CH2:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36]Br)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].C(Cl)[Cl:39]>C(N(CC)CC)C.[OH-].[Na+]>[ClH:39].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36][N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]3[C:15](=[O:16])[CH2:14][C:13]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:12]=4[CH2:11][CH2:10]3)[CH2:2]2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCCNC1)CC2
Reactant: ClCCl
Reactant: COc1ccc(CCBr)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CCCCC(CN3CCc4cc(OC)c(OC)cc4CC3=O)C2)cc1OC
Product: Cl

Procedure:
660 mg (2 mmol) of 3-[(hexahydro-azepin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 540 mg (2.2 mmol) of 2-(3,4-dimethoxyphenyl)-ethylbromide are refluxed for 1 hour in 3 ml of triethylamine. The reaction mixture is cooled and taken up in methylene chloride and 2-molar sodium hydroxide solution. The alkaline phase is separated off and extracted twice with methylene chloride. The combined organic phases are dried over magnesium sulphate and evaporated down in vacuo. Purification is carried out by column chromatography over 100 g of aluminium oxide (activity II, eluant: methylene chloride+0.3% ethanol). The fractions obtained are concentrated by evaporation in vacuo, the residue is dissolved in acetone and the hydrochloride is precipitated using ethereal hydrochloric acid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C(Cl)Cl>[CH3:22][S:23]([O:1][C@H:2]1[CH2:5][C@@H:4]([CH2:6][NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])[CH2:3]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](OS(C)(=O)=O)C1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Inter-mediate 10, tert-butyl [(cis-3-hydroxycyclobutyl)methyl]carbamate (3 g, 15 mmol) and triethylamine (5.2 mL, 36 mmol) were dissolved in CH2Cl2 (50 mL). MsCl (1.4 mL, 18 mmol) was added dropwise under stirring and cooling with an ice bath in argon. The temperature was brought to ambient within 1 h. Water (50 mL) was added, and the layers were separated. The organic one was washed with water, brine, dried with Na2SO4, and evaporated. The title compound (3.5 g, 85%) was obtained as a yellow oil. This crude product was used for the next stage without additional purification. 1H NMR-data (DMSO-d6): 6.74-7.00 (m, 1H, NH); 4.73-4.86 (m, 1H); 3.10 (s, 3H, MS); 2.97 (t, 2H, CH2, J=5.7 Hz); 2.32-2.42 (m, 2H); 1.80-2.43 (m, 3H); 1.38 (s, 9H, Boc).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[CH3:14][O-:15].[Na+].[Na]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([O:15][CH3:14])[CH:6]=[CH:5]2
Reactant: C[O-]
Reactant: Cc1cc(Br)cc2ccc(Cl)nc12
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ccc2cc(Br)cc(C)c2n1

Procedure:
A solution of 6-bromo-2-chloro-8-methylquinoline (10.7 g) in methanol (80 cm3) was heated under reflux with a solution of sodium methoxide [made from sodium 2.76 g) in methanol (50 cm3)]for 24 hours. The cooled solution was then evaporated in vacuo and the residue was partitioned between chloroform (100 cm3) and water (50 cm3). The aqueous phase was further extracted with chloroform (2×50 cm3) and the combined and dried (MgSO4) organic phases were evaporated in vacuo to give a solid which was recrystallised from ethyl acetate:hexane, 1:9, to afford 6-bromo-2-methoxy-8-methylquinoline, m.p. 89°-91° (8.3 g).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.C(OC([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCNCC2)nc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
Ethyl 6-chloronicotinate (1.12 g) was dissolved in DMF (30 mL), and 1-tert-butoxycarbonylpiperazine (1.24 g) and potassium carbonate (1.00 g) were added thereto. The mixture was stirred at 80° C. for 18 hr. Water (100 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine and dried. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added thereto at room temperature. The mixture was stirred for 2 hr and the reaction mixture was concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was basified with aqueous sodium hydrogen carbonate solution. The mixture was extracted with chloroform. The extract was dried and the mixture was concentrated under reduced pressure to give 1-(5-ethoxycarbonyl-2-pyridyl)piperazine (1.17 g) as an oil.