Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]1([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:10]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: N#CC1CCC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(c2cc(Cl)nc(Cl)n2)CCC1
Reaction time: 3 h
Yield: 11.8 %

Procedure:
To a stirring solution of 2,4,6-trichloropyrimidine (1.00 g, 5.45 mmol) and cyclobutanecarbonitrile (0.53 mL, 5.5 mmol) in anhydrous THF (27 mL) at −78° C. and under nitrogen was added lithium bis(trimethylsilyl)amide (6.0 mL, 6.0 mmol, 1.0 M solution in THF) over 3 min. The cooling bath was removed after 5 further min, and stirring continued for 3 h. The reaction was quenched by the addition of sat. aq. NH4Cl, extracted with CH2Cl2 and organics dried over MgSO4. Following concentration, the reaction residue was purified by flash column chromatography (100:0 heptanes/EtOAc-85:15 heptanes/EtOAc) to afford the title compound as a colorless solid (0.147 g, 12%); 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 2.97-2.82 (m, 2H), 2.82-2.67 (m, 2H), 2.51-2.35 (m, 1H), 2.35-2.16 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18](=[O:34])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][C:20]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]>>[CH3:16][O:17][C:18](=[O:34])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:9]([CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])=[CH:21][C:20]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Reactant: CCCS(=O)(=O)NCCC1CCCCC1
Product: CCCS(=O)(=O)N(CCC1CCCCC1)Cc1ccc(C(=O)OC)c(-c2ccccc2C)c1

Procedure:
The desired product was prepared using the method described in Example 1174B starting with N-(2-cyclohexylethyl)-N-propanesulfonylamine, prepared as in Example 1187A, and 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1178A-D. m/e (ESI) 472 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[NH:15][CH2:14][CH:13]2[C:23]([O:25][CH3:26])=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl.O>[Cl:34][CH2:35][C:36]([N:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH2:18][N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:10])=[O:11])[CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:14]1)=[O:37]
Reactant: COC(=O)C1CNc2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C1CN(C(=O)CCl)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 24.9 %

Procedure:
To a mixture of 2.5 g (6.64 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate (Reference Example 12) and 4.63 ml (33.2 mmol) of triethylamine in 40 ml of CH9Cl2 cooled to 0° C. was added to 1.65 g (14.63 mmol) of chloroacetyl chloride. The solution was stirred at room temperature for 2 days, chilled to 0° C. and 926 μl of triethylamine and 750 mg of chloroacetyl chloride were added thereto. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 and H2O. The insoluble solid was filtered off. The organic layer of the filtrate was separated, washed with brine, dried with Na2SO4 and filtered through diatomaceous earth. The solvent was removed and the residue triturated with ethyl acetate and a trace of ethanol. Chilling and filtering gave 0.75 g of methyl 1-(chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzo-diazepine-3-carboxylate (Reference Example 91). Anal. for C20H21ClN2O6S: Calc'd: C,53.0; H,4.7; N,6.2; Found: C,51.6; H,4.6; N,5.7; Mass Spectrum (ES): 453.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:10]([CH:11]=1)[CH2:9][C@H:8]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19](OC(C)(C)C)=O)[CH2:15][CH2:14]1)[O:7]2)([O-:3])=[O:2].FC(F)(F)C(O)=O.C(N(CC)CC)C.[F:40][C:41]([F:51])([F:50])[C:42]1[CH:49]=[CH:48][C:45](C=O)=[CH:44][CH:43]=1.[B-]C#N.[Na+].C(O)(=O)C>>[N+:1]([C:4]1[N:5]=[C:6]2[N:10]([CH:11]=1)[CH2:9][C@H:8]([CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:45]3[CH:48]=[CH:49][C:42]([C:41]([F:51])([F:50])[F:40])=[CH:43][CH:44]=3)[CH2:17][CH2:18]1)[O:7]2)([O-:3])=[O:2]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@H]2Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](CN1CCN(Cc3ccc(C(F)(F)F)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
A mixture of tert-butyl (S)-4-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 394 (100 mg, 0.27 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (1 ml, 7.17 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), and the solution was added 4-trifluoromethylbenzaldehyde (148 mg, 0.85 mmol), sodium cyanotrihydroborate (53 mg, 0.85 mmol), and acetic acid (49 μl, 0.85 mmol) in this order followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=1/1) to afford (S)-6-nitro-2-[4-(4-trifluoromethylbenzyl)piperazin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (53 mg, yield 46%) as a light yellow powder.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[CH:16]([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24]>>[CH2:1]([S:8][C:9]1[C:10]([CH:16]([F:18])[F:17])=[C:11]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: FC(F)c1c(Br)cccc1SCc1ccccc1
Product: O=C1CCCN1c1cccc(SCc2ccccc2)c1C(F)F
Reaction time: 8 h

Procedure:
Intermediate 55 (2.008 g, 6.1 mmol) was coupled with pyrrolidin-2-one (0.623 g, 7.32 mmol) in close analogy to the procedure described in step 1.6). After workup the crude oil crystallized upon standing overnight and was then triturated with MTBE.
Reaction SMILES: ClC1C=CC([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)C(=O)C)=C(F)C=1.FC1C=CC(C(Cl)=O)=CC=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([NH2:8])[CH2:13][C@@H:14]2[CH3:32])=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3F)C[C@@H]2C)cc1
Agent: O=C(Cl)c1ccc(F)cc1
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N)C[C@@H]2C)cc1

Procedure:
N-(4-chloro-2-fluorophenyl)-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide was made following general procedure G, substituting 4-methoxybenzoyl chloride for 4-fluorobenzoyl chloride. The amine-aryl coupling was performed differently to what is described in procedure G. Therefore (2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (obtained from the hydrogenation step, 200 mg, 0.6 mmol, 1 equ.) was dissolved in ethylene glycol dimethyl ether (1 mL) in a Schlenk tube. To this solution was added sequentially 1-bromo-4-chloro-2-fluorobenzene (105 uL, 0.84 mmol, 1.4 equ.), cesium carbonate (274 mg, 0.84 mmol, 1.4 equ.), palladium acetate (16 mg, 0.024 mmol, 0.04 equ.) and 2-(Dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (23 mg, 0.048 mmol, 0.08 equ.). The reaction mixture was flushed with nitrogen and heated to 95° C. in the Schlenk tube for 48 h. Reaction mixture was concentrated to leave a residue which was partitioned between water and ethyl acetate and extracted. The aqueous layer was separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a black oil. The crude product was purified by silica gel chromatography (methylene chloride/methanol: 100/0 to 99/1 gradient) to provide (2S,4R)-N-(4-chloro-2-fluorophenyl)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (60 mg, 24%).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:26][C:25](=[O:27])[NH:24][CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:26][C:25](=[O:27])[NH:24][CH2:23]1)=[O:19]
Reactant: [H][H]
Reactant: O=C1C[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CN1
Agent: [Pd]
Solvent: CO
Product: O=C1C[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CN1
Yield: 93.4 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-N-{[(3R)-5-oxopyrrolidin-3-yl]oxy}-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 129 (0.22 g, 0.59 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated at 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)-6-hydroxy-7-oxo-N-{[(3R)-5-oxopyrrolidin-3-yl]oxy}-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 130 (0.156 g, 93%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]CC)=[O:15])[C:5](=[O:13])[N:6]([CH:10]([CH3:12])[CH3:11])[C:7]=1[CH2:8][CH3:9].ClC1C=C(C(OCC)=O)C(=O)N(C(C)C)C=1C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5](=[O:13])[N:6]([CH:10]([CH3:12])[CH3:11])[C:7]=1[CH2:8][CH3:9]
Reactant: CCOC(=O)c1cc(Cl)c(CC)n(C(C)C)c1=O
Agent: CCOC(=O)c1cc(Cl)c(C)n(C(C)C)c1=O
Product: CCc1c(Cl)cc(C(=O)O)c(=O)n1C(C)C

Procedure:
The title compound was prepared according to the procedure of Example 1(7), but using ethyl 5-chloro-6-ethyl-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in 2(2) instead of ethyl 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:48])[NH:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:48])[NH:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)[N:27]=2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
To a suspension of 3-t-butyldiphenylsilyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (590 mg, 0.860 mmol) (obtained as described in Reference Example 53(6)) in anhydrous tetrahydrofuran (18 ml) were added successively acetic acid (59 μl, 1.03 mmol) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (1.03 ml, 1.03 mmol) in an ice bath, and the mixture was stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and water. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (95:5) as the eluant to afford 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (378 mg, yield 98%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=O.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.O>C1(C)C=CC=CC=1>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[N:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[N:30]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:33])[F:32])=[CH:25][CH:26]=3)[N:31]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c2cccnc2c(-c2cccc(C(F)(F)F)c2)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
A suspension of 2-(3-trifluoromethylbenzoyl)nicotinic acid (1.5 g) and 4-trifluoromethylphenylhydrazine (1.34 g) in toluene was stirred at reflux temperature for 3 hours (water was removed azeotropically from the mixture).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:11]=[CH:10][NH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1.CN(C=O)C>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:9]3[CH:10]=[CH:11][C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[CH:8]3)(=[O:35])=[O:36])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=C(NC1CC1)c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NC4CC4)c3)ccc2n1CC1CCOCC1
Yield: 51.3 %

Procedure:
Following the same procedure in Example 29, using N-cyclopropyl-1H-pyrrole-3-carboxamide (49 mg, 0.33 mmol) (see following step B for preparation), sodium hydride (100 mg, 60%, 2.5 mmol) and 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (122 mg, 0.33 mmol) in THF (6 mL) and DMF (0.5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 82 mg (51%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.50-0.56 (m, 2 H), 0.69-0.76 (m, 2 H), 1.40-1.57 (m, 4 H), 1.59 (s, 9 H), 2.29 (m, 1 H), 2.67-2.76 (m, 1 H), 3.24-3.34 (m, 2 H), 3.84-3.93 (m, 2 H), 4.41 (d, J=7.42 Hz, 2 H), 6.64 (dd, J=3.32, 1.56 Hz, 1 H), 7.27 (dd, J=3.32, 2.34 Hz, 1 H), 7.78-7.82 (m, 1 H), 7.90 (d, J=9.0 Hz, 1 H), 7.94 (dd, J=8.6, 1.5 Hz, 1H), 8.25 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=484.7; Anal. Calcd for C25H32N4O4S+1.10 TFA+0.10H2O (611.88): C, 53.40; H, 5.49; N, 9.16. Found: C, 53.44; H, 5.53; N, 9.18.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.[F:20][C:21]([F:39])([F:38])[C:22]1[N:27]=[C:26]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:29]([NH:28][C:26]4[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:38])([F:20])[F:39])[N:27]=4)=[O:30])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2cc(CO)n3ncnc(N)c23)cc1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CO)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Yield: 7.1 %

Procedure:
A solution of [4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methanol (170.0 mg, 0.67 mmol), phenyl [6-(trifluoromethyl)pyridin-2-yl]carbamate (281.9 mg, 1.00 mmol), and triethylamine (0.46 mL, 1.33 mmol) in DMF (5 mL) was stirred at rt for 3 d. The crude reaction mixture was purified directly by HPLC using a gradient of 20-90% MeCN in water to yield 21.1 mg (7%) of the title compound. 1H-NMR (DMSO-d6) 9.89 (bs, 1H), 9.72 (bs, 1H), 8.05-7.98 (m, 2H), 7.89 (s, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.51-7.49 (m, 1H), 7.40 (d, J=8.6 Hz, 1H), 6.64 (s, 1H), 5.19 (t, J=5.7 Hz, 1H), 4.74 (d, J=5.6 Hz, 3H); MS [M+H]+=444.1; LCMS RT=2.63 min.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].C(Cl)Cl.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20]>CCCCCC>[Br:12][C:13]1[CH:18]=[C:17]([N+:7]([O-:8])=[O:6])[C:16]([F:19])=[CH:15][C:14]=1[CH3:20]
Reactant: O=[N+]=O
Reactant: Cc1cc(F)ccc1Br
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To a mixture of nitronium tetrafluoroborate (11.6 g; 87.0 mmol) and CH2Cl2 (60.0 mL) was added 2-bromo-5-fluoro toluene (15.0 g, 10.0 mL, 79.0 mmol) over 5 min. After refluxing for 4.5 h, the mixture was cooled to room temperature and poured into ice water (150 mL). The mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give 18.3 g of crude product. The crude product was treated with hexane and cooled to −70° C. then the hexane was decanted away from the resulting solid to give the desired product as a semi-solid (9.77 g, 53% yield). The mother liquors were concentrated in vacuo and purified by flash column chromatography (eluent: 2% EtOAc in Hexane) to give the desired product (1.0 g). 1H NMR (CDCl3) δ 8.26 (d, J=6.9 Hz, 1H), 7.20 (d, J=11.7 Hz, 1H), 2.48 (s, 3H).
Reaction SMILES: C([Li])CCC.[CH:6](=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23]>>[F:16][C:17]1[C:18]([F:23])=[CH:19][CH:20]=[CH:21][C:22]=1[CH:6]([OH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Fc1ccccc1F
Reactant: CCCCCCCCC=O
Agent: [Li]CCCC
Product: CCCCCCCCC(O)c1cccc(F)c1F

Procedure:
Quantities: n-butyllithium (50 cm3, 10.0M in hexanes, 0.5 mol), nonanal (71 g, 0.5 mol) and 1,2-difluorobenzene (57 g, 0.5 mol). The experimental procedure was as described in Example 16.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:20]([C:21]5[CH2:22][N:23]([CH3:26])[NH:24][CH:25]=5)=[CH:19][N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]4=[N:16][CH:17]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O>C1COCC1>[CH3:26][N:23]1[CH2:22][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([CH2:11][CH:8]4[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]4)[CH:13]=3)[N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[CH:19]=2)=[CH:25][NH:24]1
Reactant: CN1CC(c2cn(COCC[Si](C)(C)C)c3ncc(CC4CCC5(CC4)OCCO5)cc23)=CN1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN1CC(c2cn(COCC[Si](C)(C)C)c3ncc(CC4CCC(=O)CC4)cc23)=CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of 87 (307 mg, 0.64 mmol) in THF (20 mL) was added 6.0 N aq. HCl solution (7 mL) and the reaction mixture was allowed to stir at r.t. for 1 h. Water (50 mL) was then added, and the mixture extracted with AcOEt (2×75 mL). The combined organic solutions were dried (MgSO4) and concentrated to afford 88 as a clear oil (261 mg, 0.59 mmol, 93%). 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9H), 0.99 (t, J=8.2 Hz, 2H), 1.49-1.62 (m, 2H), 2.07-2.16 (m, 2H), 2.31-2.49 (m, 5H), 2.82 (d, J=6.7 Hz, 2H), 3.65 (t, J=8.3 Hz, 2H), 4.07 (s, 3H), 5.77 (s, 2H), 7.49 (s, 1H), 7.69 (s, 1H), 7.83 (s, 1H), 7.92 (s, 1H), 8.27 (s, 1H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=1)=[O:7]>C(O)(=O)C.S(=O)(=O)(O)O>[OH:7][C:6]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)[N:14]=[N:1][CH:5]=1
Reactant: O=N[O-]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc2nncc(O)c2cc1OC
Temperature: 80 °C
Yield: 87.3 %

Procedure:
The starting material, 4-hydroxy-6,7-dimethoxycinnoline was obtained by adding a solution of sodium nitrite (1.9 g, 27 mmol) to a solution of 2-amino-4,5-dimethoxyacetophenone (5 g, 0.025 mol) in acetic acid (90 ml) and sulphuric acid (15 ml) at a rate to maintain the temperature below 20° C. The mixture was heated at 80° C. for 90 minutes. After cooling and concentrating the solution to half its original volume, the residue was poured into ether (800 ml). The solid was collected by filtration and suspended in water (200 ml). After adjusting to pH7 with sodium hydroxide the solid was filtered, washed with water, methanol and methylene chloride to give 4-hydroxy-6,7-dimethoxycinnoline (4.5 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][C:3]=1[NH:17][C:18]([C:20]1[S:24][C:23]2[CH2:25][C:26]([CH3:30])([CH3:29])[C:27](=[O:28])[C:22]=2[CH:21]=1)=[O:19].C(O)C.[BH4-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])([CH3:16])[O:9]2)=[CH:4][C:3]=1[NH:17][C:18]([C:20]1[S:24][C:23]2[CH2:25][C:26]([CH3:30])([CH3:29])[CH:27]([OH:28])[C:22]=2[CH:21]=1)=[O:19]
Reactant: CC1(C)Cc2sc(C(=O)Nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3F)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)Cc2sc(C(=O)Nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3F)cc2C1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 27 (800 mg, 1.86 mmol) and ethanol (5.0 mL). Sodium borohydride (69 mg, 11.82 mmol) was added in one portion. The mixture was stirred at room temperature for 1 h and then neutralized with acetic acid to pH 7. The reaction was concentrated under reduced pressure and triturated with ethyl acetate (10 mL) to give a quantitative yield of 28 as a white semi-solid: 1H NMR (500 MHz, CDCl3) δ 8.75 (d, 1H, J=8.5 Hz), 7.78 (s, 1H). 7.53 (m, 2H), 7.10 (m, 1H), 4.58 (s, 1H), 2.88 (d, 1H, J=16.0 Hz), 2.69 (d, 1H, J=16.0 Hz), 1.32 (s, 12H), 1.20 (d, 611, J=6.5 Hz); MS (APCI+) m/z 431.4 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
3,4-Dibenzyloxybenzaldehyde (27) (22.0 mmol) was suspended in 100 mL of anhydrous methanol and cooled to 0° C. under argon. Sodium borohydride (33.0 mmol) was added in portions to the suspension and stirred for 1 h at the same temperature. The resulting solution was then stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in ice-water and neutralized with HCl. The solution was then extracted with chloroform and the organic layer was washed successively with water, 10% NaHCO3 solution in water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to dryness to provide pure 3,4-Dibenzyloxybenzyl alcohol (28) in 97.5% yield.