Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:20]=[C:19]([C:21]3[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[NH2:28][C:22]1[N:23]=[C:24]([NH:27][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH:25]=[CH:26][C:21]=1[C:19]1[O:18][N:17]=[C:16]([CH2:15][C:12]2[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:20]=1
Reactant: COCC(=O)Cl
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Reaction time: 2 h
Yield: 6.9 %

Procedure:
To a mixture of 3-(3-(6-benzyloxy-pyridin-3-ylmethyl)-isoxazol-5-yl)-pyridine-2,6-diamine (40 mg, 0.11 mmol) described in Example 25 and dichloromethane (1 mL) were added triethylamine (22 μL, 0.16 mmol) and methoxyacetyl chloride (15 mg, 0.14 mmol) at room temperature, which was stirred for 2 hours at the same temperature. The solids that precipitated in the reaction mixture were filtered out. Tetrahydrofuran was added to the solid thus obtained, and this mixture was filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.4 mg, 7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:19])[C:6]([CH3:18])=[C:7]([OH:17])[C:8]=2[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[O:3]1.C(OCC)(=[O:23])C>[Pd]>[OH:3][C:2]([CH3:20])([CH3:1])[CH2:11][CH2:10][C:9]1[C:4](=[O:23])[C:5]([CH3:19])=[C:6]([CH3:18])[C:7](=[O:17])[C:8]=1[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)=CCc1c(O)c(C)c(C)c2c1CCC(C)(C)O2
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CC1=C(C)C(=O)C(CCC(C)(C)O)=C(CCC(C)C)C1=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,2,7,8-tetramethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol (68 mg) in ethyl acetate (2.4 mL) was added Pd/C (26 mg, 5% w/w). The resulting suspension was flushed with hydrogen gas, the container sealed, and the contents stirred under 1 atm of hydrogen gas for 30 min. The mixture was then filtered and concentrated in vacuo. The resulting residue was dissolved in acetonitrile-water (5:1, 2.6 mL) and the solution cooled to 5° C. in an ice-water bath. Into the reaction mixture was added a solution of cerium(IV) ammonium nitrate (287 mg) in acetonitrile-water (1:4, 1.6 mL) over a period of 5 minutes. The reaction mixture was allowed to stir for an additional 5 minutes, after which it was poured into a separatory funnel containing dichloromethane (30 mL) and water (30 mL). The aqueous layer was removed and the remaining organics were washed once with 1.0 M sodium chloride solution (30 mL). The organics were subsequently dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (18% ethyl acetate-82% hexanes) provided 29 mg of 2-(3-hydroxy-3-methyl-butyl)-5,6-dimethyl-3-(3-methyl-butyl)-[1,4]benzoquinone. 1H NMR (CDCl3, 400 MHz) 2.53 (m, 2H), 2.43 (m, 2H), 1.99 (s, 3H), 1.62 (m, 1H), 1.53 (m, 2H), 1.24 (m, 8H), 0.94 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]3[CH:25]=[C:24]([CH2:26][CH2:27][C:28]4[S:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[N:32]=4)[CH:23]=[CH:22][N:12]3[C:13](=[O:21])[C:14]=2/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[CH2:4]1)=[O:2]>C(O)C.[Pd]>[CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]3[CH:25]=[C:24]([CH2:26][CH2:27][C:28]4[S:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[N:32]=4)[CH:23]=[CH:22][N:12]3[C:13](=[O:21])[C:14]=2[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:4]1)=[O:2]
Reactant: COC(=O)/C=C/c1c(N2CCCC(C=O)C2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1c(N2CCCC(C=O)C2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Reaction time: 48 h
Yield: 29.4 %

Procedure:
The methyl (E)-3-{2-(3-formylpiperidino)-8-[2-(4-isopropyl-1,3-thiazol-2-yl)-ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (80.9 mg, 0.158 mmol) obtained in (A) was dissolved in ethanol (3 ml), added with 5% palladium/carbon (30 mg) and stirred at 1 atm for 2 days under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by preparative TLC (chloroform:methanol=100:2) to obtain the title compound (23.1 mg, 28%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])([CH3:5])[CH3:4])#[N:2].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:17])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-(1-cyano-1-methylethyl)benzoic acid (9.87 g, 52.2 mmol) in toluene (150 mL) was added thionyl chloride (25.3 g, 213 mmol), and the mixture was stirred at 120° C. for 2 hr. The reaction mixture was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)benzoyl chloride as a colorless oil. To a solution of 4-methyl-3-nitroaniline (7.63 g, 50.2 mmol) in pyridine (150 mL) were added N,N-dimethylpyridine-4-amine (122 mg, 1.00 mmol) and 3-(1-cyano-1-methylethyl)benzoyl chloride, and the mixture was stirred at room temperature for 14 hr. To the reaction mixture was added 1N hydrochloric acid (200 mL), and the mixture was extracted with ethyl acetate (150 mL, 100 mL). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL), and dried over anhydrous magnesium sulfate. After filtration through a silica gel pad, the filtrate was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)-N-(4-methyl-3-nitrophenyl)benzamide as a yellow oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1.[F:36][C:37]([F:56])([F:55])[C@H:38]([O:45][C:46](=[O:54])[C:47]1[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].CN(C1C=CC=CN=1)C>C1COCC1.C(N=C=NC(C)C)(C)C>[F:36][C:37]([F:55])([F:56])[C@H:38]([O:45][C:46]([C:47]1[CH:48]=[CH:49][C:50]([O:34][C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:3]3[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:20])([F:18])[F:19])=[C:7]([F:8])[C:2]=3[F:1])=[CH:28][CH:29]=2)=[O:35])=[CH:51][CH:52]=1)=[O:54])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(O)cc1)C(F)(F)F
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCCC[C@@H](OC(=O)c1ccc(OC(=O)c2ccc(-c3ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c3F)cc2)cc1)C(F)(F)F
Reaction time: 24 h
Yield: 65 %

Procedure:
To a solution of 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid (14 A) (1 equi.), (4-hydroxy benzoic acid (R)-1-trifluoromethyl-heptyl ester (7) (1 equi.), and DMAP (dimethylaminopyridine) (0.1 equi.) in THF (25 mL/mmole), DIC (diisopropyl carbodiimide) (1.2 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) gave 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid 4-[(R)-1-trifluoromethyl-heptyloxycarbonyl]-phenyl ester (15A) as a white solid (65%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([Cl:17])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C1C=CC=CC=1>[C:4]([C:3]1[C:2]([Cl:1])=[CH:15][C:14]([CH2:16][Br:36])=[CH:13][C:12]=1[Cl:17])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(C(=O)c2ccccc2)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1c(Cl)cc(CBr)cc1Cl
Yield: 57.7 %

Procedure:
A refluxing solution of 2,6-dichloro-4-methylbenzophenone (3.44 g, 13.0 mmol) and dibenzoylperoxide (325 mg, 1.34 mmol) in benzene (130 ml) was treated in portions with N-bromosuccinimide (2.75 g, 15.5 mmol). After 3 hours at reflux, the mixture was cooled and evaporated under vacuum. The residue was triturated with diethyl ether (150 ml), filtered, and evaporated under vacuum. The residue was chromatographed on a column of silica gel (250 g) eluted with 4:1 (v/v) hexane-dichloromethane to provide 2.58 g (58%) 4-benzoyl-3,5-dichlorobenzyl bromide, m.p. 111°-113° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([Si:4]([CH3:20])([CH3:19])[O:5][CH2:6][CH:7]([OH:18])[CH2:8][CH2:9][O:10][Si:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:3].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:18][CH:7]([CH2:8][CH2:9][O:10][Si:11]([CH3:17])([CH3:16])[C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:6][O:5][Si:4]([CH3:20])([CH3:19])[C:2]([CH3:21])([CH3:1])[CH3:3])(=[O:32])=[O:31]
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)CO[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of 2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-3,10-disiladodecan-6-ol (i.e. the product of Step A) (36.31 g, 0.109 mol) in dichloromethane (300 mL) cooled to about 0° C. under nitrogen, was added triethylamine (22.8 mL, 0.163 mol), followed by dropwise addition of a solution of methanesulfonyl chloride (10.14 mL, 0.13 mol) in dichloromethane (100 mL), maintaining the reaction mixture below 10° C. The reaction mixture was stirred for another 30 minutes, and then washed with citric acid (about 200 mL, 10%), water (about 200 mL) and sodium bicarbonate (about 200 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a yellow oil (42.16 g) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[N+:35]([C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@@H:50]([NH2:52])[CH3:51])[C:41]([O:43][CH3:44])=[O:42])([O-:37])=[O:36]>CN(C=O)C.CCOC(C)=O>[N+:35]([C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@@H:50]([NH:52][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:51])[C:41]([O:43][CH3:44])=[O:42])([O-:37])=[O:36]
Reactant: COC(=O)c1ccc(OC[C@H](C)N)c([N+](=O)[O-])c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.8 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (591 mg, 1.23 mmol), methyl (S)-3-nitro-4-(2-amino-1-propoxy)benzoate (313 mg, 1.23 mmol), and Et3 N (257 mL, 1.84 mmol) in DMF (5 mL) was stirred at room temp for 2 days. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 310 mg (46%) methyl (S)-3-nitro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenyl acetylamino]-1-propoxy]benzoate as a gum. 1H-NMR (CDCl3) δ 1.28 (d, 3 H, J=6.8 Hz), 2.31 (s, 3 H), 3.49 (s, 2H), 3.71 (s, 3 H), 3.92 (s, 3 H), 4.14–4.16 (m, 2 H), 4.38–4.41 (m, 1 H), 5.88–5.90 (m, 1 H), 6.49 (s, 1 H), 6.70–6.71 (m, 1 H), 6.77–6.79 (m, 1 H), 7.05–7.30 (m, 4 H), 7.55–7.57 (m, 1 H), 8.02–8.06 (m, 2 H), 8.16–8.19 (m, 1 H), 8.51–8.52 (m, 1 H); MS (FAB) m/z 551 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:8]=[C:9]=[O:10])([CH3:7])[CH3:6].[C-]#N.[CH2:16]([NH:20][CH3:21])[CH2:17][CH2:18][CH3:19]>C1C=CC=CC=1>[CH2:16]([N:20]([CH3:21])[C:9]([NH:8][C:5]([CH3:7])([CH3:6])[C:4]1[CH:11]=[CH:12][CH:13]=[C:2]([Cl:1])[CH:3]=1)=[O:10])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNC
Reactant: CC(C)(N=C=O)c1cccc(Cl)c1
Agent: [C-]#N
Solvent: c1ccccc1
Product: CCCCN(C)C(=O)NC(C)(C)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 88.7 %

Procedure:
3.9 g of m-chloro-α,α-dimethylbenzyl isocyanate prepared from the corresponding cyanide in the same way as in Synthesis Example 1, was added to a solution of 1.8 g of N-n-butyl-N-methylamine in 20 ml of benzene and the mixture vigorously stirred. After allowing the mixture to stand overnight, the reaction solution was washed with a 2N aqueous hydrochloric acid solution, a 2N aqueous sodium hydroxide solution and water in that order, and the organic layer was dried over sodium sulfate. The layer was concentrated by evaporating off the solvent to obtain crystals, which were recrystallized from n-hexane to obtain 5.0 g of the title compound as crystals.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:23]1[CH:27]2[CH2:28][CH:29](Br)[CH:25]([CH2:26]2)[CH2:24]1>O>[CH:25]12[CH2:26][CH:27]([CH2:28][CH2:29]1)[CH2:23][CH:24]2[O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: BrC1CC2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CC2CCC1C2
Temperature: 80 °C
Yield: 87.2 %

Procedure:
Isovanillin (50 g, 0.328 mol) is placed in a 1 liter round bottom flask which is equipped with a stir bar and reflux condensor and is charged with 500 ml of dimethylformamide. Potassium carbonate (45.3 g, 0.328 mol) is added to the reaction mixture which is heated to 80° C. At this temperature exo-2-bromonorbornane (12.57 g, 0.072 mol, 0.219 equivalents) is added and the reaction mixture is heated to 120° C. for 48 hours. The reaction is then cooled to room temperature and poured into 300 ml of water. The aqueous layer is extracted with ethyl ether (3×100 ml). The ethereal layer is washed with 1N sodium hydroxide solution (4×100 ml), water (3×100 ml) and saturated sodium chloride solution (3×100 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 15.47 g of a green/brown oil. The crude product is purified by flash chromatography using a gradient eluent system of ethyl acetate/hexane [10% ethyl acetate/hexane→20% ethyl acetate/hexane] to yield 7.76 g (14.4%) of the aldehyde as a white solid. MP: 75.5° C.-79.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:14])[CH2:6][NH:7]2.[C:15]([O-])([O-])=[O:16].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[C:11]([O:16][CH3:15])=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:14])[CH2:6][NH:7]2
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(c(OC)c1)C(=O)CN2
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(c(OC)c1OC)C(=O)CN2
Yield: 21 %

Procedure:
Compound (9) was synthesized from (8) in the same manner as described for the synthesis of (6) using 2-amino-4,5,6-trimethoxy-a-chloroacetophenone (1.05 g, 4.0 n-mmol), K2CO3 (838 mg, 6.1 mmol), a little KI, and dry acetone (50 ml). Purification by column chromatography (eluent: CH2Cl2/MeOH: 9/1) afforded (9) (190 mg, 21%) as red crystals.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([OH:13])[C:10]3[CH2:14][CH2:15][CH2:16][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:13][C:11]2[C:10]3[CH2:14][CH2:15][CH2:16][C:9]=3[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:12]=2)=[CH:20][CH:19]=1
Reactant: Oc1nc(-c2ccccc2)nc2c1CCC2
Reactant: Fc1ccc(CBr)cc1
Product: Fc1ccc(COc2nc(-c3ccccc3)nc3c2CCC3)cc1

Procedure:
The title compound was prepared from 2-phenyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (which was obtained in Intermediate 5) and 4-fluorobenzyl bromide according to Method A; LC retention time 3.26 min; MS: m/z (ESI) 321 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.Cl.[F:29][CH:30]1[CH2:33][NH:32][CH2:31]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[F:29][CH:30]1[CH2:33][N:32]([C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:27])[CH2:31]1
Reactant: FC1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 3-fluoroazetidine hydrochloride (30.8 mg, 276 mmol), diisopropylethylamine (241 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 3 hours at 70° C. under nitrogen atmosphere in a closed vessel and then over the weekend at room temperature. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording 4-(3-fluoroazetidine-1-carbonyl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (111 mg, 93.3%) as an insoluble white solid. mp.: 259-262° C. MS: m/z=420.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH2:28][CH3:29]>C(#N)C>[F:19][C:2]([F:1])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:27][CH2:28][CH3:29])[CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4]
Reactant: CCCI
Reactant: O=C(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(c2cccc(C(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-iodopropane (0.01 g). MS m/z (rel. intensity, 70 eV) 317 (M+, 3), 289 (15), 288 (bp), 248 (4), 109 (6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[CH3:14][Si:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][OH:18]>C1COCC1>[CH3:14][Si:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][O:18][C:12](=[O:13])[NH:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: C[Si](C)(C)CCO
Reactant: O=C=Nc1cc([N+](=O)[O-])ccc1F
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 50 °C
Reaction time: 11 h
Yield: 75.8 %

Procedure:
To a solution of 1-Fluoro-2-isocyanato-4-nitro-benzene (9.82 g, 54 mmol) in THF (40 ml) at 23° C. under an atmosphere of argon was added 2-Trimethylsilanyl-ethanol (7.72 ml, 54 mmol). The resulting mixture was stirred for 11 hours then heated to 50° C. for 2 hours. The reaction mixture was allowed to cool to 23° C. quenched with saturated NaHCO3 (aq) and extracted with EtOAc (3×100 ml). The pooled ethyl acetate was washed with 1N HCl (aq) (2×90 ml) water (90 ml) and brine (90 ml), dried with Na2SO4, filtered and concentrated to a yellow solid. Silica gel chromatography (2:8 ethyl acetate-hexane) provided (2-Fluoro-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (12.3 g, 77%). 1H NMR (300 MHz, CDCl3) δ 9.06 (dd, 1H, J=6.89 Hz, J=2.63 Hz), 7.89 (m, 1H), 7.20 (m, 1H), 6.91 (bs, 1H), 4.31 (t, 2H, J=8.67 Hz), 1.06 (t, 2H, J=8.67 Hz), 0.05 (s, 9H). LCMS (ESI−) [M+H]/z Calc'd 299, found 299.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:25]1([C:31]2([CH2:34][NH2:35])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:35][CH2:34][C:31]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[CH:11][CH:10]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: NCC1(c2ccccc2)CC1
Product: O=C1COc2c(C(O)CNCC3(c4ccccc4)CC3)ccc(O)c2N1

Procedure:
Prepared from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 147 mg (1 mmol) C-(1-phenyl-cyclopropyl)-methylamine. Final purification by chromatography (silica gel; dichloromethane/methanol gradient). Yield: 30 mg (8%); mass spectroscopy: [M+H]+=355.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([CH2:7][C:8]1[C:9]([CH3:22])=[N:10][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:13]=1)=[CH2:6])[CH3:2].CCOC(C)=O.[C:30]([OH:33])(=[S:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH2:6][S:32][C:30](=[O:33])[CH3:31])[CH2:7][C:8]1[C:9]([CH3:22])=[N:10][C:11]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CC(O)=S
Reactant: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)Cc1ccc(NC(=O)OC(C)(C)C)nc1C
Temperature: 25 °C
Reaction time: 64 h
Yield: 87 %

Procedure:
TEA (0.556 mL, 3.99 mmol) was added to a solution of 2-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (1.23 g, 3.84 mmol) in thioacetic acid (10 mL) at 0 ° C. under argon. The mixture was stirred at room temperature for 64 h. EtOAc was added and the solution was washed with Na2CO3 and brine, dried and concentrated under reduced pressure. Flash chromatography (toluene/EtOAc, 5:1→1:1) gave 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-yl)-propionic acid ethyl ester (1.33 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CC[Mg+].[Br-].[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[C:16](=[NH:17])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: N#Cc1ccc(Cl)cc1Cl
Agent: CC[Mg+]
Agent: [Br-]
Product: N=C(Nc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
Under argon, 4-chloroaniline (6.67 g, 52.5 mmol) was slowly added to EtMgBr (52 mL, 1 M in THF, 52 mmol) portion wise. After the solution was stirred for 0.5 h, 2,4-dichlorobenzonitrile (9.03 g, 52.5 mmol) was added. The resulting solution was stirred at rt overnight. The reaction mixture was carefully quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated. Crude product (16.26 g,) was obtained as a sticky brown foam which was used without purification for the next step. LC-MS m/z 299.3 (MH+), retention time 1.75 min (MDLC 1); 1H NMR (300 MHz, CDCl3) δ 4.92 (2H, br), 7.09-7.51 (7H, m).