Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([O:22][CH2:23][C@H:24]([NH:28]C(OC(C)(C)C)=O)[C:25](O)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH2:28][C@@H:24]([CH2:23][O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]([NH:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:14][CH:13]=1)=[O:26]
Reactant: Nc1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(OC2CCCCC2)cc1
Yield: 50 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(cyclohexyloxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(cyclohexyloxy)phenyl)propanamide (200 mg, 50%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=4)[C:29]([C:38](=[O:51])[C:39]4[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=4)=[CH:28]3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC(=O)NC1(CCC2C=CC(CCCN3C4C(=CC=CC=4)C(C(=O)C(F)(F)F)=C3)=CC=2)COC(C)(C)OC1)(C)(C)C>>[NH2:7][C:8]([CH2:9][OH:10])([CH2:13][OH:12])[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[C:29]([C:38]([C:39]3[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=3)=[O:51])=[CH:28]2)(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(CCC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Agent: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCn3cc(C(=O)C(F)(F)F)c4ccccc43)cc2)COC(C)(C)OC1
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(CCC(N)(CO)CO)cc3)c2c1
Yield: 65 %

Procedure:
When the product of Step E was substituted for tert-butyl-2,2-dimethyl-5-(4-(3-(3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl)propyl)phenethyl)-1,3-dioxan-5-ylcarbamate in Example 11, Step F, the identical process afforded the title compound in 65% yield, as colourless solid. 1H-NMR (D2O) 1.65-1.68 (m, 2H); 2.44-2.46 (m, 2H); 3.50 (s, 3H); 3.56 (s, 3H); 3.59 (s, 6H), 6.10 (d, 1H, J=8.77 Hz); 6.55 (broad s, 2H); 6.98 (s, 2H); 7.18-7.20 (m, 2H); 7.60-7.62 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[O:3]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(OC(C)C)(C)C>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:13](=[O:15])[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[O:3][C:4]=3[CH:10]=2)=[O:16])[CH2:25][CH2:24]1
Reactant: COc1cccc(CC2CCNCC2)c1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Solvent: CC(C)OC(C)C
Product: COc1cccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)oc4c3)CC2)c1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid (Example 43e) and 4-(3-methoxy-benzyl)-piperidine [U.S. Pat. No. 3,632,767 (1972)] according to the method described in Example 2. Melting Point: 110-115° C. (diisopropylether)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:13][OH:14]>C(O)C>[Cl:1][C:2]1[C:3]([CH3:11])=[C:4](/[C:8](=[N:13]\[OH:14])/[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: CC(=O)c1cccc(Cl)c1C
Agent: Cl
Solvent: CCO
Product: C/C(=N/O)c1cccc(Cl)c1C
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
1-(3-Chloro-2-methyl-phenyl)-ethanone (390 mg, 2.3 mmol) was dissolved in ethanol (6 ml) and hydroxylamine hydrochloride (433 μL, 10.4 mmol) was added. The mixture was stirred at 80° C. for 1.5 hours. Reaction mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate and concentrated in vacuo to give (1Z)-1-(3-chloro-2-methylphenyl)ethanone oxime as a yellow oil (383 mg, 2.08 mmol, 90% yield). 1H NMR (400 MHz, CDCl3): 6.95-7.37 (m, 3H), 2.36 (s, 3H), 2.26 (s, 1H), 2.21 (s, 3H); MS (EI) for C9H10ClNO: 184 (MH+).
Reaction SMILES: [Cl:1][C:2]1[O:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:9][N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[C:11]1=[O:17]>C(O)(=O)C>[Cl:1][C:2]1[O:8][C:5]([CH:6]=[N:9][N:10]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[C:11]2=[O:17])=[CH:4][CH:3]=1
Reactant: NN1CCNC(=O)C1=O
Reactant: O=Cc1ccc(Cl)o1
Solvent: CC(=O)O
Product: O=C1NCCN(N=Cc2ccc(Cl)o2)C1=O
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
1.6 pts. by wt. of 5-chloro-furfural, 1.3 pts. by wt. of 1-amino-2,3-dioxo-piperazine and 7 pts. by vol. of glacial acetic acid are warmed to 90° C. for 10 minutes and then left for 30 minutes at RT. The precipitate is filtered off, washed first with 3 pts. by vol. of glacial acetic acid and then twice with 10 pts. by vol. of acetonitrile each time and dried in air. 1.8 pts. by wt. (74.6%) of 1-(5-chloro-furfurylidene-amino)-2,3-dioxo-piperazine are obtained as yellowish crystals of decomp. pt. 233°-6° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17](Br)=[C:16]([CH3:21])[N:15]([CH:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH3:23])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:34][CH:35]([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>C(#N)C.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][S:2]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([CH:35]([F:45])[F:34])[CH:41]=3)=[C:16]([CH3:21])[N:15]([CH:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH3:23])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1C(C)c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1C(C)c1ccc(C#N)cc1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (preparation 11, 110 mg, 0.208 mmol), 3-difluoromethyl-phenylboronic acid (48 mg, 0.28 mmol), palladium (0) tetrakis(triphenylphosphine) (32 mg, 0.028 mmol) in acetonitrile (2 mL) is added 2 M aqueous K2CO3 solution (0.21 mL, 0.42 mmol). After stirring for 18 h at 75° C., the reaction mixture is diluted with methanol, acidified with acetic acid and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1% TFA, 60° C.). Yield: 90 mg (75% of theory); ESI mass spectrum: [M+H]+=576; Retention time HPLC: 1.03 min (Z018_S04).
Reaction SMILES: O.[OH-].[Ca+2:3].[OH-].[P:5](=[O:9])([OH:8])([OH:7])[OH:6]>C(O)(=O)C>[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Ca+2:3].[Ca+2:3].[Ca+2:3].[P:5]([O-:9])([O-:8])([O-:7])=[O:6]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
A new and useful method for producing commercial tri-calcium phosphate, or TCP, utilizes less water and energy than current methods. TCP has the following chemical formula: Ca3(PO4)2. The processes &the present invention produce a TCP product with less energy and less waste than the current methods. According to the method of the present invention in FIG. 1, water 1, hydrated lime 2, related ingredients such as acetic acid 4, and phosphoric acid 3 are admixed in a reaction vessel 7 to form a tri-calcium phosphate slurry 6. The resultant slurry 6 has approximately 72% water and 28% by weight of solid TCP. The slurry 6 then physically contacts air to remove the moisture from the slurry 6. To remove the moisture, the air temperature must reach the evaporation point of the moisture in the slurry 6. The heat of the chemical reaction is controlled to produce TCP having certain characteristics, such as fine particle or powdery form.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=3)=[CH:3][CH2:2]1.[H-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.[Cl-].[NH4+]>CN(C)C=O>[O:1]1[CH2:6][CH2:5][C:4]([C:7]2[N:8]([CH2:27][C:26]3[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=3)=[CH:3][CH2:2]1
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)c1ccc2[nH]c(C3=CCOCC3)cc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(C1=CCOCC1)n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of the compound obtained in Example 14 (4) (16.5 mg) in N,N-dimethylformamide (3 ml), 60% sodium hydride (3.6 mg) was added under nitrogen atmosphere at 0° C. and the mixture was stirred for 30 minutes, followed by additin of 4-fluorobenzyl bromide (22.7 mg), and the mixture was stirred at 15 to 30° C. for 15 hours. The reaction solution was then poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 18.4 mg of the desired product as a white powder.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](F)[N:11]=1.[H-].[Na+].O>O1CCCC1>[CH2:1]([O:8][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(F)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(OCc2ccccc2)n1
Temperature: 50 °C
Yield: 100 %

Procedure:
An oven-dried 3-neck 2 L round bottom flask under nitrogen was charged with benzyl alcohol (9.04 ml, 87 mmol) and tetrahydrofuran (75 ml). Attached an addition funnel containing a solution of 2,6-difluoropyridine (10.00 g, 87 mmol) in tetrahydrofuran (30 ml). Sodium hydride (3.82 g, 96 mmol) was added in small portions with stirring. Heated in a 50° C. oil bath for 45 minutes; cooled to room temperature. Added contents of addition funnel dropwise. After 18 hours poured into water. Extracted three times with ethyl acetate, washed combined organic portions with brine, dried with anhydrous magnesium sulfate, filtered and rotary evaporated filtrate. The crude product was subjected to flash column chromatography eluting with hexane. Evaporation of fractions gave the title compound as a colorless oil. (17.70 g, 87 mmol, 100% yield). LCMS (ES+) m/z 204.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@:12]1(C)[C@H:15]([CH:16]2OCOO2)[N:14](C(=O)C(OC)=O)[C:13]1=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[OH:30].[K+].[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH2:29][OH:30])[NH:14][C:13]1=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: COC(=O)C(=O)N1C(=O)[C@](C)(NC(=O)OCc2ccccc2)[C@@H]1C1OCOO1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@H]1C(=O)N[C@@H]1CCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of methyl 2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(1,2,4-trioxolan-3-yl)-methylazetidin-1-yl]-2-oxoacetate (205 mg) in methanol (4 ml) was added 1N aqueous potassium hydrogen carbonate (0.5 ml) at ambient temperature. The mixture was stirred for 25 minutes and cooled to 0° C. Sodium borohydride (40 mg) and 1N aqueous potassium hydrogen carbonate were added to the mixture at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and at ambient temperature for an additional 30 minutes, and quenched by addition of acetic acid (0.20 ml). The resulting mixture was concentrated under reduced pressure and the residue was dissolved in chloroform and washed with brine containing sodium hydrogen carbonate. The aqueous layer was extracted three times with chloroform. The combined extracts were dried over magnesium sulfate, evaporated in vacuo, and chromatographed on silica gel (3 g, eluting with 10-30% acetone in dichloromethane) to give 66 mg of (3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](I)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].CS(C)=O.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=4)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1-c1cccc(F)c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 76.7 %

Procedure:
To a 10 mL round-bottomed flask was added N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 21) (0.0820 g, 0.162 mmol), DMSO (2.50 mL, 35.2 mmol), 3-fluorophenylboronic acid (0.0272 g, 0.194 mmol, Aldrich, St. Louis, Mo.), and sodium carbonate (0.405 mL, 0.809 mmol, 2 M). The mixture was carefully evacuated and backfilled with N2. To the mixture was added trans-dichlorobis(triphenylphosphine)palladium(II) (0.011 g, 0.0162 mmol, Strem Chemical, Inc., Newburyport, Mass.). Again, the mixture was carefully evacuated and backfilled with N2. The mixture was stirred at 90° C. for 40 min, allowed to cool to rt. and then directly purified by preparative HPLC (Phenomenex Gemini 5 micron (Phenomenex, Torrance, Calif.), C18, 100×30 mm, 5 to 75% CH3CN(0.1% TFA)/H2O(0.1% TFA) over 20 min then 100% CH3CN(0.1% TFA) for 3 minutes at 20 mL/min) with the fractions containing suspected product concentrated to afford the title compound as a yellow solid (0.059 g, 62%). MS (ESI, positive ion) m/z: 475 (M−TFA+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 3H), 3.20 (s, 3H), 7.25-7.28 (m, 1H), 7.53-7.60 (m, 1H), 7.70-7.75 (m, 1H), 7.77-7.81 (m, 1H), 8.02 (d, J=9.6 Hz, 1H), 8.32 (d, J=9.6 Hz, 1H), 8.52 (d, J=2.2 Hz, 1H), 8.95 (d, J=2.2 Hz, 1H), 9.92 (s, 1H), 10.24 (s, 1H).
Reaction SMILES: C[C:2]1([C:11]2[CH:16]=[CH:15][C:14](C(F)(F)F)=[CH:13][CH:12]=2)OC2C=CC=CC=2[O:3]1.[N+]([O-])(O)=[O:22].O>ClC(Cl)C>[O:22]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:2][O:3]1
Reactant: O=[N+]([O-])O
Reactant: CC1(c2ccc(C(F)(F)F)cc2)Oc2ccccc2O1
Solvent: O
Solvent: CC(Cl)Cl
Product: c1ccc2c(c1)COO2
Temperature: 20 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 2-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-benzodioxole (5.6g) in dichloroethane (15 ml) was added over 10 minutes to vigorously stirred nitric acid (50% w/v, 25 ml) keeping the temperature at 15°-20° C. by means of a cooling bath. The resulting reaction mixture was stirred for a further 1 hour at 20° C., poured into water (200 ml) and extracted with methylene chloride (3×100 ml). After drying over anhydrous sodium sulphate, the extract was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methylene chloride as eluant, affording the pure product benzodioxole as a pale yellow oil (5.3 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](OC)=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: COC(=O)c1cc(F)cc2c1OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(F)cc2c1OCCO2
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of methyl 7-fluoro-2,3-dihydro-1,4-benzodioxine-5-carboxylate (400 mg, 1.88 mmol) in tetrahydrofuran (20 mL) was cooled to 0° C. and then added lithium aluminum hydride (3.78 mL, 1.0 M solution in tetrahydrofuran). The reaction mixture was allowed to warm to room temperature and stirred for 45 min, at which time water (143 μL) was added followed by 15% sodium hydroxide (143 μL) and then water (286 μL) again. The white precipitate was filtered and the filtrate was concentrated to give 345 mg (100%) of (7-fluoro-2,3-dihydro-1,4-benzodioxine-5-yl)methanol as a colorless oil: 1H NMR (400 MHz, CDCl3): 6.63 (dd, J=2.8, 8.8 Hz, 1H), 6.56 (dd, J=3.2, 9.2 Hz, 1H), 4.64 (d, J=6.4 Hz, 2H), 4.28-4.25 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[N:6][CH:7]=1.[CH3:17][N:18](C=O)C>CCOCC.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[N:6][CH:7]=1)#[N:18]
Reactant: CC(C)(C)OC(=O)NCc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1cncc(C#N)c1
Temperature: 110 °C
Yield: 86 %

Procedure:
To tert-butyl (5-bromopyridin-3-yl)methylcarbamate (384 mg, 1.34 mmol) in DMF (10 ml), Zn(CN)2 (94 mg, 0.80 mmol) and Pd(PPh3)4 were added and heated at 110° C. for 3 h. Then the reaction mixture was cooled to RT, diluted with ether, washed with ammonium hydroxide solution, water and brine. Crude residue was column chromatographed (40% ethylacetate/60% Hexanes) to yield tert-butyl (5-cyanopyridin-3-yl)methylcarbamate in 86% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Br:1][C:2]1[CH:18]=[CH:17][C:16]2[C:9](=[O:11])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccccc1COc1cccc(Br)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2ccccc2COc2cc(Br)ccc21
Temperature: 0 °C
Yield: 44 %

Procedure:
A suspension of 2-(3-bromophenoxymethyl)benzoic acid (35 g, 0.11 mole) in 100 mL of trifluoracetic anhydride containing 20 drops of boron trifluoride-ether complex was refluxed for four hours. The mixture was poured into ice water and then extracted with diethyl ether. Concentration of ether solution under reduced pressure and chromatography of the residue on a silica gel column (Waters Associates, Prep 500) with hexane/methylene chloride (70:30) gave the pure product (14 g), m.p. 110°-112 C. pmr (CDCL3) δ: 8.10 (d, J=9.1 Hz, 1H, H1), 7.90 (dd, J=1.4, 7.6 H, 1H, H10) 7.57 (dt, J=1.4, 7.4, 7.4 Hz, 1H, H8), 7.48 (dt, J=1.4, 7.6, 7.6 Hz, 1H, H9), 7.36 (dd, J=1.3, 7.3 Hz, 1H, H7), 7.27 (d, J=1.8 H, 1H, H4), 7.24 (dd, J=1.8, 9.1 Hz, 1H, H2), 5.18 (s, 2H, ArCH2O).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]([CH3:46])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:39]([CH3:46])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Cn1cc(C(=O)CCCCCBr)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cn(C)c3ccccc23)CC1
Yield: 41.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.2 g) as starting compound, potassium carbonate (1.8 g) and 6-bromo-1-(1-methyl-1 H-indol-3-yl)-1-hexanone (1.0 g) were reacted and treated in the same manner as in Example 172 to give 0.71 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-methyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1[C:18]([NH2:19])=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[N:12][CH:11]=1>N1C=CC=CC=1>[C:1]([NH:19][C:18]1[N:10]=[CH:11][N:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[N:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncnc2nc[nH]c12
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Reaction time: 3 h

Procedure:
Benzoyl chloride (1.3 mL, 11 mmol) was added dropwise over 30 min to a stirred suspension of adenine (1.35 g, 10 mmol) in dry pyridine, and stirring was continued at 100° C. for a further 3 h, and the reaction mixture was allowed to stand overnight at room temperature. The reaction was quenched with methanol and the solvents were removed under reduced pressure. The residue was triturated in hot isopropanol and dried in vacuo to give 8 as a white solid: yield 2.15 g (90%); MS (+ESI): m/z 240 [M+H]+; 1H NMR (400 MHz, d-DMSO): δ11.50 (s, 1H), 8.74 (s, 1H), 8.52 (s, 1H), 8.11 (d, 2H, J=7.2 Hz), 7.66 (t, 1H, J=7.2 Hz), 7.58 (t, 2H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3](=[NH:5])[NH2:4].C(O/[CH:14]=[C:15](/[C:21](=O)[CH:22]([F:24])[F:23])\[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C[O-].[Na+]>C(O)C>[F:23][CH:22]([F:24])[C:21]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:4]=[C:3]([C:2]([F:10])([F:1])[C:6]([F:9])([F:8])[F:7])[N:5]=1
Reactant: N=C(N)C(F)(F)C(F)(F)F
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Yield: 39.5 %

Procedure:
A mixture of 1.620 g (10 mmol) of 2,2,3,3,3-pentafluoropropanimidamide (commercially available) and 2.222 g (10 mmol) of ethyl (2Z)-2-(ethoxymethylidene)-4,4-difluoro-3-oxobutanoate (for preparation see WO 2005/123690) in 10 ml of absolute ethanol is stirred under reflux for 4 days after adding 0.680 g (10 mmol) of sodium methylate. The mixture is then concentrated by evaporation in vacuo and the residue is taken up in 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic phases are washed successively with 5 ml of water and 5 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. Chromatographic purification with a mixture of cyclohexane and ethyl acetate gives 1.264 g (3.95 mM, 39.5% of theory) of ethyl 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylate as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](O)=[O:27]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1cccs1
Agent: Cl
Product: O=C(CNC(=O)c1cccs1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2-thiophenecarboxylic acid.