Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)N[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[N:13]=2)[CH2:9]1)(C)(C)C.Cl.N1CC([OH:25])C1>>[Cl:18][C:14]1[N:13]=[C:12]([N:10]2[CH2:11][CH:8]([OH:25])[CH2:9]2)[CH:17]=[CH:16][N:15]=1
Reactant: OC1CNC1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccnc(Cl)n2)C1
Agent: Cl
Product: OC1CN(c2ccnc(Cl)n2)C1

Procedure:
Prepared as [1-(2-chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester using azetidin-3-ol hydrochloride. MS: [M+H]+=186
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].S(=O)(=O)(O)O.[C:18]([O-])(O)=O.[Na+]>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(O)c(OC)c1
Yield: 98 %

Procedure:
To a solution of 4-hydroxy-3-methoxybenzoic acid (0.1 g, 0.59 mmol) in 10 mL of methanol was added 0.3 mL of conc. sulfuric acid, and refluxed overnight. The pH of the solution was shifted into an alkaline zone by addition of 5% aqueous NaHCO3 solution. Following extraction with EtOAc, the extract was washed with a saturated NaCl aqueous solution. It was dried over MgSO4 and the solvent was removed by concentration under reduced pressure to afford the compound 9 (0.107 g, 98%).
Reaction SMILES: [CH3:1][C:2]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](=[O:36])[C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[CH:14][C:13]=1[CH3:37])([CH3:10])[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O>>[CH3:10][C:2]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](=[O:36])[C:21]2[S:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)=[CH:14][C:13]=1[CH3:37])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: Cc1cc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)ccc1OC(C)(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)ccc1OC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 25 h

Procedure:
2-Methyl-2-(2-methyl-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)-propyl)phenoxy)propanoic acid is prepared from tert-butyl 2-methyl-2-(2-methyl-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)propanoate according to general procedure E using 10 equivalents of trifluoroacetic acid. After stirring for 25 hours at room temperature, the reaction mixture is washed with water and then the dichloromethane is removed by evaporation under reduced pressure. The evaporation residue is purified by silica-gel chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[C:11](=[O:20])[NH:12][CH2:13][CH:14]=[C:15]([CH2:16][C:17]([OH:19])=O)[C:5]2=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:54][C:55]1[N:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=1>CN(C=O)C>[Cl:54][C:55]1[N:60]=[CH:59][C:58]([NH:61][C:17](=[O:19])[CH2:16][C:15]2[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]=3[C:11](=[O:20])[NH:12][CH2:13][CH:14]=2)=[CH:57][CH:56]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(O)CC1=CCNC(=O)c2[nH]c3ccc(F)cc3c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1=CCNC(=O)c2[nH]c3ccc(F)cc3c21)Nc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetic acid, prepared as in reference 16, (25 mg, 0.091 mmol) in DMF (1 mL) is added DIEA (35.4 mg, 0.274 mmol), HATU (38.2 mg, 0.100 mmol) and 6-chloro-pyridin-3-ylamine (35.2 mg, 0.274 mmol). The mixture is stirred at room temperature for 2 hours and concentrated. The residue is purified by HPLC (C18 column, eluted with CH3CN/H2O with 0.05% TFA) to give N-(6-Chloro-pyridin-3-yl)-2-(7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetamide; 1H NMR (DMSO-d6) δ 3.43 (t, 2H, J=5.6 Hz), 3.84 (s, 2H), 5.96 (t, 1H, J=7.2 Hz), 7.12 (dt, 1H, J1=2.4 Hz, J2=8.8 Hz), 7.43 (d, 1H, J=8.8 Hz), 7.46 (dd, 1H, J1=4.4 Hz, J2=8.8 Hz), 7.67 (dd, 1H, J1=2.4 Hz, J2=10.8 Hz), 8.01 (dd, 1H, J1=2.8 Hz, J2=8.0 Hz), 8.19 (t, 1H, J=5.2 Hz), 8.54 (d, 1H, J=3.2 Hz), 10.48 (s, 1H), 12.04 (s, 1H); m/z [M++1] 385.0.
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12]>>[C:9]1([CH3:8])[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:12][CH:3]=[CH:4][C:5](=[O:7])[CH3:6]
Reactant: COC=CC(C)=O
Reactant: Cc1ccccc1CN
Product: CC(=O)C=CNCc1ccccc1C

Procedure:
The title compound 60 is prepared according to the procedure reported in step A of Example 18 with 4-methoxy-3-buten-2-one (0.1 g, 1 mmol) and 2-methylbenzylamine (0.125 g, 1 mmol) as reactants. Yellow solid. (Yield 0.19 g, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][N:14]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:12]=2[C:27]=1[Cl:28])=[O:6].[C:29]([O-:32])(=[O:31])[CH3:30].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[C:29]([O:32][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][N:14]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:12]=2[C:27]=1[Cl:28])=[O:6])(=[O:31])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(NC(=O)NCCCl)c2Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCNC(=O)Nc1ccc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C
Temperature: 25 °C
Reaction time: 120 h

Procedure:
3.7 g 1-(2-chloroethyl)-3-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea dissolved in 100 ml of acetonitrile are treated with 1.83 g of potassium acetate and 4.21 g of 18-crown-6. The mixture is then stirred at room temperature for 5 days, concentrated, treated with water/methylene chloride and the aqueous solution is extracted several times with methylene chloride. The organic solution is dried with sodium sulphate, filtered and concentrated. The residue is purified on a 350 g silica gel column using ethyl acetate as the eluting agent and crystallised from ethanol/ether. There is obtained 2-[3-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ureido]ethyl acetate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O1CCOCC1.[Pd]>[CH3:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:2]=[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:4]=[N:5]2
Reactant: Cc1cccc2nnc(-c3ccccc3)c(Cl)c12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cccc2nnc(-c3ccccc3)cc12
Yield: 17.3 %

Procedure:
12 g (47.2 mmol) of the compound from Example VII are hydrogenated for several hours at 3 bar in the Parr apparatus in 400 ml of dioxane and 75 ml of 1N NaOH in the presence of 1.5 g of Pd-C (5% strength) with TLC checking. Solid is then filtered off with suction through kieselguhr and the filtrate is concentrated on a rotary evaporator. After chromatography on silica gel (toluene→toluene/ethyl acetate 1:1), 1.8 g (17%) of the pure title compound are obtained. M.p.: 101° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].CO>[Pd].ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(N)ccc1OC
Reaction time: 17 h

Procedure:
Combine methyl 2-methoxy-5-nitrobenzoate (13.3 g, 63 mmol) and methanol. Add 5% palladium-on-carbon (0.66 g). Hydrogenate on a pressure apparatus at 50 psi. After 17 hours, filter through celite to remove the catalyst and evaporate the filtrate in vacuo to give a residue. Combine the residue and dichloromethane and extract with water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methoxy-5-aminobenzoate. Rf=0.18 (silica gel, ethyl acetate/methanol 1/1). Elemental Analysis calculated for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.44; H, 6.04; N, 7.62.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[OH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>CC(C)=O.C(Cl)Cl>[C:4]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:15][CH2:14]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(=O)CC(=O)OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
20 ml of a 50% strength solution of diketene in acetone are added dropwise to 32.5 g of N-[2-(2-hydroxyethoxy)-ethyl]-4,4-diphenylpiperidine and about 0.1 g of N,N-dimethylaminopyridine in 200 ml of methylene chloride at the boiling point, with vigorous stirring. After boiling under reflux for 1 h, the solution is allowed to cool and is concentrated to constant weight under a high vacuum. The pale yellow viscous coil which remains is used for the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:21]#[N:22].[SiH](CC)(CC)CC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]([OH:16])=[O:15])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:21]#[N:22]
Reactant: CCc1nc2c(Cl)c(C#N)ccc2n1CC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(Cl)c(C#N)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
1,1-Dimethylethyl (4-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)acetate (0.032 g, 0.1 mmol) and Et3SiH (0.116 mg, 1 mmol) were combined in CH2Cl2/TFA (1:1; 6 mL) and stirred at rt for 5 h. Concentration was followed by pH adjustment to ca. 7 in H2O. Extraction with EtOAc, washing with brine, drying (Na2SO4), filtration, and concentration were followed by purification (SiO2, EtOAc/hexanes) to afford the title compound (0.017 g): MS (ESI) m/z 264 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[CH2:8]([C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:21]=[CH:22][C:23]([N:24]=[C:27]=[S:28])=[CH:25][CH:26]=2)[CH2:18][CH2:19]1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCC[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCCCC[C@H]1CC[C@H](c2ccc(N=C=S)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.36 ml of triethylamine in 15 ml of chloroform was treated dropwise at -10° C. with a solution of 2.18 g of p-[trans-4-(5-hexenyl)cyclohexyl]aniline in 20 ml of chloroform. After 5 minutes the mixture was treated with a solution of 690 μl of thiophosgene in 10 ml of chloroform, warmed to room temperature and stirred for 2 hours. Thereafter, the reaction mixture was partitioned between water and chloroform. The organic phase was dried over magnesium sulphate and concentrated. Chromatographic separation on 140 g of silica gel using ethyl acetate/petroleum ether (vol. 5:95) and subsequent crystallization from 80 ml of methanol and low temperature filtration gave 1.24 g of p-[trans-4-(5-hexenyl)cyclohexyl]phenylisothiocyanate (purity 100%) as a milky liquid of m.p. (C-N) 15.2° C. and cl.p. (N-I) 46.1° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.[Li+].[OH-]>O1CCOCC1>[OH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:10]([C:11]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:21][CH2:22]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-[(trans-4-Hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (34 mg, 0.075 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (1 ml) and then LiOH 1N (375 ul, 0.375 mmol) was added. After 4 hours of stirring at room temperature, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 21 mg (64%) of 3-[(trans-4-Hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 15).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C([Li])CCC.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O1CCCC1>[OH:6][C:2]([CH3:3])([CH3:1])[C:4]#[C:5][C:12]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCCCC1
Reactant: C#CC(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#CC1(O)CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
A solution of 2-methyl-3-butyne-2-ol (25 g, 0.297 mol) in tetrahydrofuran (250 ml) is cooled to −78° C. under a nitrogen atmosphere and to this solution, n-butyl lithium (1.6 molar solution in hexanes, 410 ml, 0.65 mol) is added slowly over 1.5-2.0 hours. The reaction mixture is stirred for 1 hour at −78° C. and a solution of cyclohexanone (46.2 ml, 0.44 mol) in tetrahydrofuran (46 ml) is added. The reaction mixture is stirred at −78° C. for one hour and allowed to come to ambient temperature and stirred at ambient temperature for 2-3 hours. The reaction mixture is cooled to 10° C. and quenched with ice cold water. The mixture is extracted with dichloromethane (3×250 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 1-(3-hydroxy-3-methylbut-1-ynyl)cyclohexanol (20 g) as a colourless oil.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C@@H:15]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][S:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]([F:30])=[CH:10][N:9]=1>CO.O>[C:22]([O:21][C:19](=[O:20])[CH2:18][S@:17]([CH2:16][CH:15]([NH:14][C:12]1[C:11]([F:30])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=1)[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:1])([CH3:23])([CH3:24])[CH3:25]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)OC(=O)CSC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C[S@@](=O)CC(Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxone (1.04 g, 1.69 mmol) was added to a stirring solution of (S)-tert-Butyl 2-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethyl-butylthio)ethanoate, 168a, (0.53 g, 1.41 mmol) in methanol (20 mL). The solution was stirred for 15 minutes at room temperature. The solution was concentrated to give white residue which was dissolved in water (50 mL). The aqueous layer was extracted with EtOAc (3×25 mL) and the organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 540 mg of the desired product as a white solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.05 minutes (M+H) 394.28.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][NH2:9])[CH:4]=[CH:5][N:6]=1.[C:10]1([C:16]2[O:17][C:18]3[C:19](=[C:21]([C:25](O)=[O:26])[CH:22]=[CH:23][CH:24]=3)[N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][NH:9][C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:18]3[O:17][C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:20][C:19]=23)=[O:26])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1CCN
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Product: Cc1nccn1CCNC(=O)c1cccc2oc(-c3ccccc3)nc12
Yield: 35 %

Procedure:
N-[2-(2-Methylimidazol-1-yl)ethyl]-2-phenylbenzoxazole-4-carboxamide was prepared from 2-(2-methylimidazol-1-yl)ethylamine and 2-phenylbenzoxazole-4-carboxylic acid using the conditions described in Step C of Example 1. This compound was obtained in 35% yield as a white solid; mp 125-127° C.; 1H NMR 300 MHz, CD3OD) δ 8.11 (dd, J=7.8, 1.0 Hz, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.63-7.52 (m, 3H), 7.42 (t, J=8.0 Hz, 1H), 7.13 (s, 1H), 6.86 (s, 1H), 4.22 (t, J=5.8 Hz, 2H), 3.87 (t, J=6.0 Hz, 2H), 2.34 (s, 3H); MS (APCI) m/z 347 [M+H]+
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:50][N:51]([CH3:57])[C@@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1>CN(C)C=O>[CH3:50][N:51]([CH3:57])[C@@H:52]1[CH2:56][CH2:55][N:54]([C:8]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)=[O:7])[CH2:53]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Reaction time: 4 h
Yield: 51 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added (3R)-3-dimethylaminopyrrolidine (0.050 ml) at room temperature, followed by stirring for 4 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (21.8 mg, 51%).
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: OC1(Cc2ccccc2)CCN(CCOc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 4-benzyl-4-hydroxy-piperidine (0.62 g, 3.3 mmol), 1-(2-bromoethoxy)-4-(phenylmethoxy)-benzene (1.0 g, 3.3 mmol) and potassium carbonate (0.9 g, 6.5 mmol) in 2-butanone (15 ml) was refluxed overnight. It was cooled to room temperature, 30 ml of H2O were added and the organic phase was separated. The water phase was extracted two times with ethyl acetate. The organic phases were then pooled, dried with Na2SO4 and the solvent evaporated to give 4-benzyl-1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidin-4-ol as a yellowish solid (1.35 g, 99%). MS: m/e=418.4 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[N:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[N:5]=1
Reactant: N#Cc1cccc(Cn2ccc([N+](=O)[O-])n2)c1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1cccc(Cn2ccc(N)n2)c1
Yield: 64.3 %

Procedure:
A solution of 3-(3-nitro-pyrazol-1-ylmethyl)-benzonitrile (507 mg, 2.22 mmol) in ethanol (25 mL) was hydrogenated in a Parr hydrogenator using 10% palladium on carbon (53 mg, 0.05 mmol) for 4 h at 50 psi at room temperature. The product was isolated, after filtration through a Celite plug, and purification by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 4 g; 0% to 10% methanol/dichloromethane) to afford 3-(3-amino-pyrazol-1-ylmethyl)-benzonitrile, (283 mg, 64%) as light orange solid.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH:38]([OH:40])[CH:37]([OH:41])[CH2:36]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH:38]([OH:40])[CH:37]([OH:41])[CH2:36]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCCN1CC(O)C(O)C1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CC(O)C(O)C3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]carbamic acid phenyl ester and 1-(4-amino-butyl)-pyrrolidine-3,4-diol by the procedure analogous to Example 8. HPLC ret. time: minutes. 1H NMR (400 MHz, CD3OD) δ7.20 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.8, 9.6 Hz), 5.45 (s, 2H), 3.63 (t, 4H, J=5.6 Hz), 3.28 (m), 2.74 (m, 4H), 2.68 (m, 2H), 2.25 (d, 3H, J=2.0 Hz), 1.56 (m, 4H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:16]O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: CO
Reactant: Cc1ccc(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
5-Chloro-2-methylbenzoic acid (46, 5.0 g, 29.3 mmol) was suspended in dichloromethane (30 mL) and thionyl chloride (3.2 mL, 5.2 g, 44 mmol) was added. The solution was stirred at room temperature for 1 hour. Methanol was added and the reaction was allowed to proceed for a further 16 hours. The volatile components were evaporated under reduced pressure. The resulting residue was taken up again in methanol (30 mL) and pyridine (5 mL) was added. The solution was stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to afford methyl 5-chloro-2-methylbenzoate (5.3 g, 96% yield) that was used in the following step without further purification.