Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([C:18]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)=[O:19])[CH2:3]1.[CH2:27]=[O:28].[OH-].[Na+]>C(O)(=O)C.O>[OH:28][CH2:27][N:12]1[C:11]2[C:17]3[C:14]([CH2:15][C@@H:16]4[C@@H:6]([C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:18]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)=[O:19])[CH2:3][N:2]4[CH3:1])=[CH:13]1
Reactant: C=O
Reactant: CN1C[C@H](C(=O)Nc2cnccn2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN1C[C@H](C(=O)Nc2cnccn2)C[C@@H]2c3cccc4c3c(cn4CO)C[C@H]21
Reaction time: 3 h

Procedure:
4 g of 6-Methyl-N-pyrazinylergoline-8β-carboxamide (see Example 1) dissolved in 42 ml of acetic acid are placed in a three-necked bottle and diluted with 200 ml of water. 42 ml of an aqueous formaldehyde solution (35% of weight) are added. The mixture is stirred for three hours at 60°-70°, cooled to 20°, adjusted to a pH-value of 8 with a 5N sodium hydroxide solution and extracted with methylene chloride. After evaporation of the solvent, 3.28 g of the obtained crude product, 1-hydroxymethyl-6-methyl-N-pyrazinylergoline-8β-carboxamide, are dissolved in 270 ml of absolute methanol after which 52 g tartaric acid is added and the mixture is stirred for three hours at 60°. The solvent is evaporated in vacuo. The residue is taken up in water, neutralized with a 2N potassiumbicarbonate solution and extracted with methylene chloride. The crude product, obtained after evaporation of the solvent, is purified by chromatography on a column of silica gel. The product is eluted with 3% methanol in methylene chloride and is dissolved in acetone. Two equivalents of tartaric acid are added to form the tartaric acid addition salt.
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][O:14][CH3:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl.C(OCC)(=O)C>[CH3:17][C:16]([NH:1][C@@H:2]([C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:13][O:14][CH3:15])=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
To a cold solution (−2° C.) of 1.94 g of Intermediate 6, in 40 mL of dichloromethane was added dropwise 2.12 g of acetic anhydride maintaining the temperature below 5° C. The reaction mixture was stirred at room temperature for 3 hours and the organic phase was washed with water (2×20 mL), sodium bicarbonate solution (2×20 mL), brine and dried over sodium sulfate. The solvent was removed under vacuum and a white solid was obtained. The product was dissolved in 20 mL of ethyl acetate at reflux temperature and cooled slowly to 0° C. The solid was collected by filtration and dried yielding 1.6 g of lacosamide as a white solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26](Br)=[CH:25][C:23]=3[CH:24]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])=[O:32]>O1CCOCC1.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26]([C:37]4[CH:38]=[CH:39][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:35][CH:36]=4)=[CH:25][C:23]=3[CH:24]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Br)ccc3o2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3o2)CC1
Temperature: 100 °C

Procedure:
An aqueous Na2CO3 solution (2 M, 0.68 mL) is added to a mixture of 4-(5-bromo-benzofuran-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.50 g) and 4-(methanesulfonyl)phenylboronic acid (1.97 g) in a mixture of dioxane/water (60:40). The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (500 mg) is added. The resulting mixture is heated to 100° C. for 2 h. After cooling to room temperature, ethyl acetate, brine, and activated charcoal are added. The mixture is filtered and the organic phase is separated, dried over Na2SO4, and the solvent is evaporated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) to give the title compound. LC (method 1): tR=1.80 min; Mass spectrum (ESI+): m/z=478 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31](=[O:40])[C:32]1[C:37]([Cl:38])=[CH:36][C:35](Cl)=[N:34][CH:33]=1.C1N2CCN(CC2)C1>>[CH3:29][O:30][C:31](=[O:40])[C:32]1[C:37]([Cl:38])=[CH:36][C:35]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:34][CH:33]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Agent: C1CN2CCN1CC2
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, Step 4) was reacted with methyl-4,6-dichloronicotinate and DABCO (5 h, r.t.) to give the title compound as a white solid. MS (m/e)=585.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2.S(=O)(=O)(O)O.[C:20](=O)(O)[O-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:20])=[O:13])=[CH:5]2
Reactant: O=C([O-])O
Reactant: O=C(O)c1cnc2ccc(Br)cc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc2ccc(Br)cc2c1
Temperature: 85 °C
Reaction time: 96 h

Procedure:
To a solution of 6-bromoquinoline-3-carboxylic acid (3 g, 11.9 mmol), in methanol (55 mL) was added sulfuric acid (0.32 mL, 6 mmol). The reaction was stirred at 85° C. for 96 h. The reaction was then cooled to room temperature and saturated sodium bicarbonate solution was added until pH=7. On neutralization, methyl 7-bromo-2-naphthoate precipitated as a solid which was collected by suction filtration (Int-1, 2.77 g, 97%). LC-MS: (FA) ES+ 266; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.33 (d, J=2.1 Hz, 1H), 9.01 (d, J=2.1 Hz, 1H), 8.53 (t, J=1.3, 1.3 Hz, 1H), 8.07-8.01 (m, 2H), 3.95 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([Cl:21])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].N1C(C)=CC=CC=1C>CC#N>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[C:12]([Cl:21])[CH:11]=1)[CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCNc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COC(=O)CN(CCC(=O)OC(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 115 °C
Yield: 64.1 %

Procedure:
A neat solution of 8.50 g (22.5 mmol) of 3-(3-chloro-4-trifluoromethoxy-phenylamino)-propionic acid tert-butyl ester, 10.71 ml (112.6 mmol) of methyl bromoacetate and 13.07 ml (112.6 mmol) of 2,6-lutidine was stirred 14 h at 60° C., diluted with 30 ml of CH3CN and heated at 115° C. for 20 h. The reaction was then partitioned between aqueous 10% KHSO4 solution and EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 95:5 to 85:1) to yield 5.94 g (64%) of the title compound as light yellow oil. MS: 412.11 (MH+, Cl).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:32][C:31]3[CH:34]=[CH:35][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: O=[N+]([O-])c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 1.2 %

Procedure:
The title compound (0.004 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.3 g) using 4-nitrobenzyl bromide (0.3 g) in place of benzyl chloride. MS (ESI): exact mass calculated for C20H19ClN4O2, 382.12; found, m/z 383.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.23-8.19 (m, 2H), 7.51-7.47 (m, 2H), 7.45-7.47 (m, 2H), 7.32 (d, J=8.6 Hz, 2H), 5.52 (s, 2H), 2.98-2.95 (m, 4H), 2.89-2.85 (m, 2H), 2.83-2.79 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccccc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 100° C. and MS: m/e=305 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and benzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:13][CH:12]=2)[CH2:11]1)=[O:19]
Reactant: CN=C=O
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Product: CNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1

Procedure:
The compound was prepared from 3-[4-(trifluoromethyl)phenoxy]azetidine and methylisocyanate as described in Example 3 of U.S. Pat. No. 4,226,861, m.p. 154°-157° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3=[C:23]([CH3:26])[CH:24]=[CH:25][N:12]3[N:11]=2)[C:3]=1Br.[F:28][CH:29]([F:46])[C:30]1[CH:31]=[C:32]([OH:45])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3=[C:23]([CH3:26])[CH:24]=[CH:25][N:12]3[N:11]=2)[C:3]=1[C:34]1[CH:33]=[C:32]([OH:45])[CH:31]=[C:30]([CH:29]([F:46])[F:28])[CH:35]=1
Reactant: Cc1ccn2nc(CNc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(O)cc(C(F)F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc(CNc3ncnc(N)c3-c3cc(O)cc(C(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 43.4 %

Procedure:
To a solution of 2-(((6-amino-5-bromopyrimidin-4-yl)amino)methyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.16 mmol) in dioxane (2 ml) were added 3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (67 mg, 0.25 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (13 mg, 0.02 mmol) and 246 μl of a 2M aqueous solution of cesium carbonate. The mixture was stirred under argon atmosphere at 90° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to obtain 34 mg (42% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:4][O:5][C:6]=1[Si](C)(C)C.[NH4+].[OH-]>CCO>[Br:1][C:2]1[C:3]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:4][O:5][CH:6]=1
Reactant: C[Si](C)(C)c1onc(-c2cccnc2)c1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Brc1conc1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
To a solution of EtOH (20 ml) containing compound 63 (4.5 g, 15.4 mmol) were added 5 ml of 25% NH4OH. After the addition, the resulting solution was stirred for 10 minutes at room temperature. The reaction mixture was concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether) afforded the title compound (64) as an oil (2.76 g, 82%). (TLC diethyl ether Rf 0.4). 1H-NMR (400 MHz, CDCl3): δ 9.14 (d, J=2 Hz, 1H), 8.76 (dd, J=5 Hz, 2 Hz, 1H), 8.58 (s, 1H), 8.19 (dt, J=8 Hz, 2 Hz, 1H), 7.48-7.43 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].CN(C=O)C.O=S(Cl)[Cl:25]>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([Cl:25])=[O:9])(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (70 mg, 0.26 mmol) in toluene (5 mL) were added catalytic amount of DMF and SOCl2 (0.2 mL, 2.61 mmol) and the reaction mixture was heated to reflux for 6 hours. The solvent was evaporated and the resulting 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (70 mg, crude) was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: N#CCc1cccc(N)c1
Yield: 80.5 %

Procedure:
A solution of 3-nitrobenzeneacetonitril (8.0 g) in EtOH (100 ml) was hydrogenated at 1 atm and room temperature over 5% palladium on carbon (0.8 g) for 4 hrs. The catalyst was removed by filtration through Hyflo and the filtrate was evaporated. The residue was chromatographed, eluting with EA:Hexane (1:2) to give the title compound (5.25 g) as an orange oil.
Reaction SMILES: [O:1]=[C:2]1[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[NH:3]1.[CH2:27](I)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:27]([N:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)[C:2]1=[O:1])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-n3c(=O)[nH]c4cccnc43)ccc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)c2ncccc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A mixture of tert-butyl 5-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (900 mg), ethyl iodide (418 mg) and cesium carbonate (1.25 g) in DMF (10 mL) was stirred at 50° C. for 12 h, treated with water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give tert-butyl 5-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (830 mg) as an amorphous solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[Li]CCCC.CN([CH:29]=[O:30])C>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:6]2[O:5][C:4]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:3][C:2]=2[CH:29]=[O:30])=[CH:9][CH:10]=1
Reactant: Clc1ccc(Sc2oc(C3CCOCC3)nc2Br)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc(C2CCOCC2)oc1Sc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 118.6 %

Procedure:
To a dry flask was added 4-bromo-5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole (810 mg, 2.162 mmol) and THF (21.6 mL), and the reaction mixture was cooled to 78° C. nBuLi (1.486 mL, 2.378 mmol) was added slowly and the reaction mixture was stirred at −78° C. for 5 min. DMF (0.837 mL, 10.81 mmol) was added and the reaction mixture was stirred at −78° C. for 10 min, quenched with water, allowed to warm to RT. The reaction mixture was extracted with EtOAc, washed with 3M LiCl, dried over sodium sulfate and concentrated in vacuo to give 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carbaldehyde (830 mg crude) to be used as is in the next step. MS: M+H=324.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH:13](O)[CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH2:13][CH2:12][CH:11]=1
Reactant: OC1CCC(c2cc3ccccc3o2)c2ccoc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=C(c2cc3ccccc3o2)c2ccoc2CC1
Yield: 85.3 %

Procedure:
To a mixture of 19.3 g of 4,5,6,7-tetrahydro-4-(2-benzofuryl)-benzofuran-7-ol in 400 ml of toluene was added 100 mg of p-toluene sulfonic acid, and the mixture was placed on a Rotovap®, and the solvent was distilled in vacuo (60° C.) until a residue was obtained. The residue was chromatographed on silica (hexane/methylene chloride 1.5:1) to afford 15.3 g (86%) of 6,7-dihydro-4-(2-benzofuryl)-benzofuran, (Formula III: R2 =H; ##STR9## R4 =2-benzofuryl) as an orange oil.
Reaction SMILES: [CH:1]([C@@H:3]([N:7]([CH3:15])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]([CH3:6])[CH3:5])=O.C1(P(=[CH:35][C:36]#[N:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:36](/[CH:35]=[CH:1]/[C@@H:3]([N:7]([CH3:15])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]([CH3:6])[CH3:5])#[N:37]
Reactant: CC(C)[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)[C@@H](/C=C/C#N)N(C)C(=O)OC(C)(C)C
Yield: 74.2 %

Procedure:
To a solution of tert-butyl (1S)-1-formyl-2-methylpropyl(methyl)carbamate (WO 99/32509) (500 mg, 202 mmol) in dichloromethane (5 mL) is added (triphenylphosphoranylidene)acetonitrile (700 mg, 2.32 mmol). After 1 h additional (triphenylphosphoranylidene)acetonitrile is added (350 mg, 1.16 mmol). After 24 h the reaction mixture is concentrated in vacuo and chromatographed (silica gel, hexane/ether) to give the title compound as an oil (410 mg). Analysis for C13H22N2O2: Calc'd: C, 65.52; H, 9.3; N, 11.75. Found: C, 65.3; H, 9.05; N, 11.51. MS (ES): m/z 239.1 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[C:4]([F:12])[CH:3]=1.[CH:13]1([C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:16]2[CH2:17][CH2:18][C@H:13]([C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[CH2:14][CH2:15]2)=[C:4]([F:12])[CH:3]=1
Reactant: NCCCc1ccc(Cl)cc1F
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(Cl)cc4F)CC3)cc2o1

Procedure:
Condensation of 3-(4-chloro-2-fluorophenyl)-1-propylamine (1.5 g, 6.5 mmol) and ketone 5 (1.5 g, 6.5 mmol), following the procedure described in Example 1, gave 6-{trans-4-[3-(4-chloro-2-fluorophenyl)-propylamino]cyclohexyl}-3H-benzoxazol-2-one (479 mg, 18%), as a white solid: 1H NMR (500 MHz, DMSO-d6): δ 7.36-7.32 (m, 2H), 7.22-7.20 (m, 1H), 7.13 (d, J=1 Hz, 1H), 6.99-6.94 (m, 2H), 3.70-3.00 (br s, 2H), 2.64 (t, J=8 Hz, 2H), 2.57 (t, J=8 Hz, 2H), 2.47-2.38 (m, 2H), 1.94 (br d, J=10 Hz, 2H), 1.77 (br d, J=10 Hz, 2H), 1.70-1.64 (m, 2H), 1.44 (dddd, J=13, 13, 13, 3 Hz, 2H), 1.13 (dddd, J=13, 13, 13, 3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[O:23]([CH2:30][CH:31]=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:31][CH2:30][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Reactant: O=CCOc1ccccc1
Product: CC1=C(CCON=CCOc2ccccc2)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with phenoxyacetaldehyde by the method of Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[CH:6][N:5]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1cnc(Cl)nc1N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C#N)c(N)n2)CC1

Procedure:
A mixture of 4-amino-2-chloro-pyrimidine-5-carbonitrile (2.0 g, 12.94 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 15.53 mmol, 1.2 equiv; commercially available) in anhydrous DMF (20 mL) was heated to 60° C. for 4 h. The organic phase was concentrated under reduced pressure and the crude product purified by crystallization from ethyl acetate providing 3.02 g (74%) of the title compound. MS (ISN): 317.1 [M−H]−.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(F)cc1
Product: Fc1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-fluoroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (solid, mp 215-216° C.). MS(ES+) m/z 228 ([M+1]+, 100).