Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15](N)=[O:16]>O>[O:16]=[C:15]1[NH:14][C:4](=[O:6])[C:3]2[C:2](=[CH:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=2)[NH:1]1
Reactant: NC(N)=O
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Solvent: O
Product: O=C(O)c1ccc2c(=O)[nH]c(=O)[nH]c2c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Into a round bottom flask was added 2-aminoterephthalic acid (0.83 g, 4.6 mmol) and urea (2.75 g, 45.8 mmol). The reaction mixture was heated to 160° C. and stirred overnight. The mixture was cooled to rt, water added and the solid was filtered. The solid was then washed with acetic acid to afford 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (0.87 g, 92%). LC-MS: (FA) ES+ 207.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:26]([N:28]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[CH2:38][CH2:39][NH2:40])[CH2:29][CH3:30])[CH3:27]>C(#N)C>[CH2:26]([N:28]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[CH2:38][CH2:39][NH:40][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:29][CH3:30])[CH3:27]
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
3.2 g (0.0117 mol) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 1.27 g (0.012 mol) of anhydrous sodium carbonate were heated to 60° C. for 4 hours in 100 ml of dry acetonitrile together with 3.0 g (0.014 mol) of 2-[2-[(diethylamino)-methyl]-piperidin-1-yl]ethanamine with stirring. The mixture was filtered while hot, the filtrate was cooled and the substance which crystallised out was suction filtered. 2.7 g (51% of theory) of colourless cyrstals were obtained, m.p. 175°-176° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][N:9]=[N:8][C:7]=1[CH3:11])=[O:5].[CH2:13](OCC)C.C[Mg]I>C1COCC1>[C:4]([C:6]1[S:10][N:9]=[N:8][C:7]=1[CH3:11])(=[O:5])[CH3:13]
Reactant: CON(C)C(=O)c1snnc1C
Reactant: CCOCC
Agent: C[Mg]I
Solvent: C1CCOC1
Product: CC(=O)c1snnc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of N-methoxy-N-methyl-4-methyl-1,2,3-thiadiazole-5-carboxamide (11.31 g, 60.4 mmol) in THF (100 ml) was added 2M diethyl ether solution of methylmagnesium iodide (45.3 ml, 90.6 mmol) over 0.5 h at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was quenched with saturated aqueous ammonium chloride (100 ml) and then extracted with diethyl ether (200 ml×2). The extracts were dried (MgSO4) and concentrated to give 7.49 g (87%) of the title compound as a pale brown oil.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:1][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:17])=[CH:14][CH:13]=1
Reactant: NC1CCc2ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(NC1CCc2ccccc21)c1ccc(F)cc1

Procedure:
The title compound was prepared from (rac)-1-aminoindan (1.7 g, 12.85 mmole) and 4-fluorobenzoyl chloride (2.24 g, 14.1 mmole) as in Ex. 52; 1.71 g (6.7 mmole, 52%), mp: 109°-10° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:5]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][NH:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:5]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CNC(=O)c1ccc(N)c(Oc2ccc(F)cc2F)c1
Yield: 100.3 %

Procedure:
A mixture of N-methyl-3-(2,4-difluorophenoxy)-4-nitrobenzamide (0.85 g), iron powder (0.8 g) and ammonium chloride (80 mg) in ethanol (20 ml) and water (10 ml) was refluxed with stirring for an hour. The insoluble materials were filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated to give a powder of N-methyl-4-amino-3-(2,4-difluorophenoxy)benzamide (0.77 g).
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.B([C:47]1[CH:55]=[CH:54][C:50]([C:51]([OH:53])=[O:52])=[C:49]([F:56])[CH:48]=1)(O)O.B(O)O>>[C:51]([C:50]1[CH:54]=[CH:55][C:47]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:48][C:49]=1[F:56])([OH:53])=[O:52]
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 4-borono-2-fluorobenzoic acid as the reactant boronic acid. The product was isolated as a white solid (6.46 mg, 19%). LCMS: m/e 575.54 (M−H)−, 3.88 min (method 2). 1H NMR (599 MHz, DMSO-D6_CDCl3) δ ppm 0.95 (s, 6H), 0.98 (s, 3H), 1.00 (s, 3H), 1.02 (s, 3H), 1.04-1.76 (m, 17H), 1.71 (s, 3H), 1.88 (d, J=7.03 Hz, 2H), 2.13 (dd, J=17.58, 6.44 Hz, 1H), 2.20 (d, J=12.30 Hz, 1H), 2.29-2.39 (m, 1H), 2.98-3.07 (m, 1H), 4.61 (s, 1H), 4.74 (s, 1H), 5.33 (d, J=5.27 Hz, 1H), 6.96 (d, J=11.13 Hz, 1H), 7.02 (d, J=8.20 Hz, 1H), 7.79 (t, J=7.62 Hz, 1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[CH2:23])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH2:8][NH2+:7]1)=[O:5].[NH:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:35]([O:34][C:32]([NH:24][C@H:25]([C:29]([N:7]1[CH2:8][C@H:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[CH2:23])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH2:10][C@H:6]1[C:4]([O:3][CH3:2])=[O:5])=[O:30])[CH:26]([CH3:27])[CH3:28])=[O:33])([CH3:37])([CH3:38])[CH3:36]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=Cc1ccc2ccnc(O[C@H]3C[NH2+][C@H](C(=O)OC)C3)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=Cc1ccc2ccnc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of Intermediate 1 in DMF was added Boc-(L)-Val (1.05 eq), followed by iPr2NEt (3.5 eq) and TBTU (1.05 eq). The resulting reaction mixture was stirred 12 h at RT and partitioned between EtOAc and 1N aq. HCl. The organic layer was further washed with sat. aq. NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (hexane/EtOAc=7/3) to give the title compound as a colourless oil. MS (ES+) C27H35N3O6 requires: 497. Found: 498 (M+H+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:12][CH:13]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][S:2]([O:6][CH:7]([C:8]1[CH:13]=[N:12][C:11]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])(=[O:4])=[O:3]
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (56 μl, 0.72 mmol) was added slowly to the mixture of 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid {5-[hydroxy-(2-methoxy-phenyl)-methyl]-pyridin-2-yl}-amide (50 mg, 0.12 mmol) and DIEA (24 μl, 0.14 mmol) in dichloromethane (2 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 3 h. Solvents were evaporated and the residue was used for the next step without any additional purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=[O:26])C>O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([NH2:23])=[O:26])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: O
Product: NC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Yield: 26 %

Procedure:
4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (400 mg, 1.27 mmol) was treated with polyphosphoric acid at 80° C. overnight. After allowing the mixture to cool to room temperature, ethyl acetate and water were added. The organic layer was separated. The aqueous layer was basified to pH 10 with concentrated NaOH and extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel eluting to give the title compound (88 mg, 26%). 1H NMR (400 MHz, CDCl3) δ7.29 (d, 2H), 6.91 (d, 2H), 5.64-5.30 (d, 2H), 4.02 (t, 2H), 3.76 (t, 4H), 2.62 (t, 2H), 2.52 (m, 4H), 2.37-2.30 (m, 2H), 2.08-1.96 (m, 4H), 1.81-1.75 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(Cl)CCl.[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>C(Cl)Cl>[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:29]
Reactant: Cc1cnccc1C(=O)O
Reactant: Cc1ccc(-c2cccnc2)cc1-c1ccc(N)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cnccc1C(=O)Nc1ccc(-c2cc(-c3cccnc3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
Amide Coupling Reaction: To a solution of 2′-methyl-5′-(pyridin-3-yl)biphenyl-4-amine n (40 mg, 0.15 mmol) in DCM (3 mL) was added EDC (85 mg, 0.45 mmol) and 3-methylisonicotinic acid (40 mg, 0.3 mmol). The solution was stirred at room temperature for 6 hr before it was concentrated and chromatographied to give Compound 20 (50 mg, 88%).
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=O)=[CH:13][CH:12]=1>>[C:1]1(=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCC1
Reactant: COc1ccc(C(=O)c2ccc(C#N)cc2)cc1
Product: COc1ccc(C(=C2CCCCCC2)c2ccc(C#N)cc2)cc1
Yield: 56.3 %

Procedure:
The general McMurry protocol, described for 14 was employed. The coupling was conducted between cycloheptanone (1.5 mL, 12.64 mmol), and 4-{[4-(methyloxy)phenyl]carbonyl}benzonitrile (1.0 g, 4.2 mmol) to afford 0.750 g (56%) of the title compound 207 as a white solid. IR (film): 2920, 2225, 1603, 1508, 1242, 825, cm1. 1H NMR (300 MHz, CDCl3): δ 7.58 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 3.80 (s, 3H), 2.36 (br s, 2H), 2.29 (br s, 2H), 1.60 (s, 8H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].[CH2:12](OS(OCC)(=O)=O)[CH3:13]>CN(C)C=O>[CH2:12]([N:1]1[C:5]2[C:4](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:3]=[CH:2]1)[CH3:13]
Reactant: c1cnc2[nH]cnc2c1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cnc2ncccc21
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
To a flask were added 0.5 g 4-azabenzimidazole and 10 ml N,N-dimethylformamide and the mixture was cooled to 10 C under nitrogen. 0.18 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 0.71 g Diethylsulfate were added and the mixture was allowed to warm to 22 C and was stirred for 16 hours. The mixture was quenched slowly with 30 ml 1M hydrochloric acid and the aqueous layer was washed with ethyl acetate. After basification with sodium hydroxide, the product was extracted twice with ethyl acetate and dried over sodium sulfate. Following filtration and solvent removal, the product was purified by silica gel chromatography using 5% methanol in ethyl acetate to 12% methanol in ethyl acetate. 0.4 g Of an oil was obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]([NH:27][C:28](=O)[O:29]C(C)(C)C)[CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]3[C:11](=[CH:12][N:13](COCC[Si](C)(C)C)[N:14]=3)[CH:10]=2)[NH:5][CH:6]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH:48]1[CH2:53][CH2:52][CH:51]([N:54]2[CH2:63][C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[NH:56][C:55]2=[O:64])[CH2:50][CH2:49]1>C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:7]([NH:27][C:28]([N:48]2[CH2:49][CH2:50][CH:51]([N:54]3[CH2:63][C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[NH:56][C:55]3=[O:64])[CH2:52][CH2:53]2)=[O:29])[CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([CH3:18])[CH:17]=2)[NH:14][N:13]=[CH:12]3)[NH:5][CH:6]=1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nc(Br)c[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nc(Br)c[nH]2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 72 h

Procedure:
tert-Butyl 1-(4-bromo-1H-imidazol-2-yl)-2-(7-methyl-2-((2(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (19.0 mg, 0.035 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.0 mL) (1.0 mL). The mixture was stirred under nitrogen for 3 days. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (6.2 mg, 0.038 mmol, 1.1 equiv) and N′N-diisopropylethylamine (25.0 μL, 4.0 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (10.1 mg, 0.038, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 7.3 mg, (36%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.50-1.71 (m, 4H), 2.55 (s, 3H), 2.74-2.93 (m, 2H), 3.16-3.25 (m, 2H), 4.03-4.20 (m, 4H), 4.78 (m, 1H), 5.12-5.19 (m, 1H), 6.63 (d, J=7.9, 1H), 6.94 (d, J=7.9, 1H), 6.94-7.00 (m, 2H), 7.04 (s, 1H), 7.12 (s, 1H), 7.12 (d, J=7.3, 1H), 7.16 (dd, J=7.6, 7.6, 1H), 7.40 (s, 1H), 7.99 (s, 1H). Mass spec.: 577.67 (MH)+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH:5]1[CH:6]=[CH:7][C:8]2N[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1.[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>C(O)(=O)C.O>[CH:5]1[CH:6]=[CH:7][C:8]2[N:1]([C:2]([NH2:4])=[O:3])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1.[S:20](=[O:22])(=[O:21])([OH:24])[OH:23]
Reactant: NC(N)=O
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 27.5 °C

Procedure:
To a suspension of urea (400 g, 6.66 mols) in acetic acid (500 ml), sulphuric acid (15 ml) was added, followed by iminostilbene (100 g, 0.518 mols), under stirring at 25-30° C. The resulting reaction mixture was heated to 80-85° C. and maintained for a period of 7-8 hours, and the reaction was monitored by thin layer chromatography (TLC). The reaction mass was diluted with water, and the resulting carbamazepine product (m.p. 188-189° C.) separated by filtration, washed with water until neutral and dried at 90-100° C. until constant weight. The identity of the product was further verified by tlc (toluene/methanol 18/03, uv=254 nm) to be identical to the reference compound and by infra-red spectroscopy (KBr) Vmax=3466, 1677, 1605, 1595 cm−1.
Reaction SMILES: [C:1](=[O:8])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])[NH2:2].[CH2:9]=[C:10]([CH3:12])[CH3:11]>C(O)CCC>[C:10]([NH:2][C:1](=[O:8])[O:3][CH2:4][CH2:5][CH2:6][CH3:7])([CH3:12])([CH3:11])[CH3:9]
Reactant: C=C(C)C
Reactant: CCCCOC(N)=O
Solvent: CCCCO
Product: CCCCOC(=O)NC(C)(C)C
Temperature: 70 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
A stirred mixture of 117 g of butyl carbamate, 5 g of butanol, 17 g of ®LEVATIT SPC-118 and 160 g of a mixture comprising 49 percent by weight of isobutene, 41.5 percent by weight of n-butenes and 9.5 percent by weight of butanes was heated to 70° C. in a stirred autoclave, and stirring was continued at this temperature for 5 hours. Thereafter, the catalyst was separated off and the mixture was distilled under reduced pressure. 149 g (86% of theory) of butyl N-tert.-butylcarbamate of boiling point 110°-111° C./20 mbar were obtained. No substantial amount of diisobutene was detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:13])([F:12])[F:11].[CH3:27][O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30]>>[CH3:27][O:28][C:29]([C:31]1([C:34]2[CH:35]=[CH:36][C:37]([CH2:40][O:26][C:4]3[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=3)=[CH:38][CH:39]=2)[CH2:33][CH2:32]1)=[O:30]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CC1
Product: COC(=O)C1(c2ccc(COc3ccc(C(C)C(O)(c4cnc5ccccc5c4)C(F)(F)F)c(Cl)c3)cc2)CC1

Procedure:
In analogy to Example 140, step 6, 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenol (Example 140, step 5) was reacted with 1-(4-bromomethyl-phenyl)-cyclopropanecarboxylic acid methyl ester (CAS 873372-30-6) to give the title compound as an off-white solid. MS (m/e)=570.4 [M+H+].
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: O=C1CC[C@@H](CO)O1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CC[C@@H](COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (1.0 g, 8.6 mmol, Acros) in dichloromethane (10 mL) were added 3,4-dihydro-2H-pyran (0.94 mL, 10.3 mmol, Aldrich) and pyridinium p-toluenesulfonate (0.22 g, 0.86 mmol, Aldrich). After stirring at room temperature overnight, the reaction mixture was washed with water (5 mL) and brine (5 mL). The organic extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to obtain 1.6 g (93%) of the title compound. MS (DCI/NH3) m/z 218 (M+NH4)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:5]([CH3:21])=[N:4]1)[CH3:2].[C:22]([C:30](O)=[O:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)CCl>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([N:8]([CH2:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[C:30](=[O:31])[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([CH3:21])=[N:4]1)[CH3:2]
Reactant: CCn1cc(NCCc2ccc(C(F)(F)F)nc2)c(C)n1
Reactant: O=C(O)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCn1cc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)C(=O)c2ccccc2)c(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of (1-ethyl-3-methyl-1H-pyrazol-4-yl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (100 mg) in CH2Cl2 (5 mL) was added under a nitrogen atmosphere at 0° C. benzoyl formic acid (1.1 eq., commercially available) and EDC (1.1 eq). After stirring for 12 h a rt, the mixture was washed with aqueous Na2CO3 (saturated, 2.5 mL) and water (2.5 mL), the combined aqueous layers were extracted with CH2Cl2 (3×2.5 mL) and the combined organic layers dried over sodium sulfate. Concentration afforded the title compound (161 mg, >100%) as a light yellow oil which was used without further purification for the next step. MS m/e: 431.2 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([Br:24])[CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClCCOC(Cl)=O.ClC(OC=C)=O.O>ClC(Cl)C>[Br:24][C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:15]=1)[N:22]=[CH:21][CH:20]=[CH:19]2
Reactant: Brc1cc(N2CCN(Cc3ccccc3)CC2)c2ncccc2c1
Agent: C=COC(=O)Cl
Agent: O=C(Cl)OCCCl
Solvent: CC(Cl)Cl
Solvent: O
Product: Brc1cc(N2CCNCC2)c2ncccc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of 8-(4-benzyl-piperazin-1-yl)-6-bromo-quinoline (1.6 g, 4.2 mmol) in dichloroethane (50 mL) under a N2 atmosphere was added chloroethylchloroformate (1.26 mL, 12.6 mmol) and the reaction mixture was heated at 80° C. for 4 hours, and at ambient temperaure overnight. No reaction was observed by TLC, therefore vinyl chloroformate (0.35 mL, 6.3 mmol) was added and the reaction was heated at 80° C. for another 4 hours. The cooled reaction was poured into H2O and extracted into CH2Cl2 (2×100 mL) and EtOAc (100 mL). The organic fractions were combined, dried over Na2SO4, and left in EtOAc overnight. The organic layer was concentrated and purified by column chromatography 10%MeOH/CH2C2+NH4OH) affording 1.03 g (84%) of a brown foam. MS(+)APCI m/z 292 [M+H]+.