Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), β-alanine (1.06 g, 11.9 mmol) and NaOMe solution (18 mL, 8.96 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude residue was dissolved in saturated NaHCO3 and washed with ether. 1 M HCl was added to the aqueous layer until pH was about 1, and the resulting precipitate was isolated by filtration to give 21 mg of the title compound as a white solid. MS: (+) m/z 393.00 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:14]([OH:17])[CH:15]=[CH2:16].[H-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH2:14]([O:17][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1)[CH:15]=[CH2:16]
Reactant: Clc1nccnc1N1CCOCC1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCOc1nccnc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
120 g of 2-chloro-3-morpholinyl-pyrazine and 70 g of allyl alcohol are dissolved in 640 ml of hexamethylphosphoric acid triamide. 28.8 g of sodium hydride are introduced into this solution over the course of 30 minutes at 0° C. The mixture is then stirred for a further hour at 0° C. and thereafter for 1 hour at 30° C. and 15 hours at room temperature, until the reaction has subsided. The reaction mixture is then poured out onto 2 liters of ice water. After the excess sodium hydride present has been decomposed, the mixture is extracted by shaking with ether. The ether extracts are washed with water until neutral, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue is distilled in a high vacuum. 2-Allyloxy-3-morpholinyl-pyrazine, boiling point 105°-106° C./0.03 mm Hg, is thus obtained.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[C:29]1([C:35]([NH2:38])([CH3:37])[CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:38][C:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:37])[CH3:36])=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)(N)c1ccccc1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC(C)(C)c3ccccc3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 2-phenylpropan-2-amine via General Procedure E to give 7.4 mg of 303 following reverse phase purification. MS (Q1) 497.2 (M)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:11]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 97.1 %

Procedure:
3-Nitro-phenol (1.00 g, 7.189 mmol) was treated with benzyl bromide (1.352 g, 7.91 mmol), and K2CO3 (1.242 g, 8.986 mmol) in DMF. The reaction mixture was heated to 100° C. for 1 hr at which time the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (1.6 g, 97%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29]1
Reactant: CN(C)C1CNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC(N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N,N-dimethylazetidin-3-amine 1H NMR (500 MHz, DMSO-d6) δ ppm 2.33 (d, J=1.95 Hz, 3 H) 2.81 (s, 6 H) 4.07-4.21 (m, 1 H) 4.29 (br. s., 2 H) 4.47-4.59 (m, 1 H) 4.66 (m, J=7.80 Hz, 1H) 7.63 (br. s., 1 H) 7.71-7.78 (m, 1 H) 7.91-8.81 (m, 4 H). ESI-MS m/z [M+H]+ 421.3.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=4[O:24][CH3:25])[N:14]=3)=[CH:9][CH:8]=2)[CH2:3]1.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:25][O:24][C:19]1[CH:18]=[C:17]([O:26][CH3:27])[CH:16]=[C:15]2[C:20]=1[C:21](=[O:23])[NH:22][C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:35](=[O:37])[CH3:36])[CH2:3]3)=[CH:8][CH:9]=1)=[N:14]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N)C4)cc3)nc2c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NC(C)=O)C4)cc3)nc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A solution of 2-(4-(3-aminopyrrolidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.41 mmol) in CH2Cl2 (10 mL) was treated with Et3N (0.114 mL, 0.82 mmol), cooled to 0° C., and acetyl chloride (0.029 mL, 0.41 mmol) was added. The mixture was stirred for 2 hours at room temperature, concentrated, and purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH. The mixture was further purified by flash chromatography on silica gel, eluting with 9:1 methylene chloride/methanol, to afford the title compound (0.130 g, 78%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 11.67 (s, 1H), 8.18 (d, J=6.8 Hz, 1H), 8.14 (d, J=6.8 Hz, 2H), 6.66 (d, J=2.3 Hz, 1H), 6.60 (d, J=9.0 Hz, 2H), 6.44 (d, J=2.3 Hz, 1H), 4.36-4.39 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.13-3.59 (m, 5H), 2.15-2.22 (m, 1H), 1.90-1.94 (m, 1H), 1.82 (s, 3H). ESI MS m/z 409 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[C:19]([O:20][CH2:21][C@@H:22]([NH:27]C(=O)OC(C)(C)C)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:6]2[N:7]([CH3:17])[C:8](=[O:16])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][C:10]=3[CH3:15].Cl.O1CCOCC1>CO>[NH2:27][C@@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:21][O:20][C:19]1[C:3]([CH:2]([F:1])[F:35])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(C(F)F)cc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)c(C(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a solution of (S)-tert-butyl (1-((9-(difluoromethyl)-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (500 mg, 0.480 mmol) in MeOH (10 mL) at 0° C. was added 4N HCl in 1,4-dioxane (20 mL, 80 mmol). The solution was warmed to room temperature and stirred for 2 h. The mixture was then was concentrated under reduced pressure. The residue was taken up in EtOAc and the EtOAc layer was washed with saturated aqueous NaHCO3 then H2O, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep. HPLC to afford (S)-8-((2-amino-4-methylpentyl)oxy)-9-(difluoromethyl)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (60 mg, 0.149 mmol, 31% yield) as pale yellow solid. LC/MS (ESI) m/e 390.2 [(M+H)+, calcd for C21H26F2N3O2, 390.2]; LC/MS retention time (method A): tR=2.09 min; HPLC retention time (method A): tR=10.1 min; HPLC retention time (method B): tR=9.18 min; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.73 (s, 1H), 8.66 (s, 2H), 7.07-7.41 (m, 2H), 4.66-4.53 (m, 1H), 4.52-4.49 (m, 1H), 3.78-3.89 (m, 4H), 3.22 (s, 3H), 1.74-1.88 (m, 2H), 1.63-1.71 (m, 1H), 1.04 (m, 6H).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[CH2:9](O)[CH2:10][CH2:11][CH3:12].O>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O:5][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCCCO
Reactant: CCP(=O)(O)CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOP(=O)(CC)CCO
Yield: 85.8 %

Procedure:
414 g (3 mol) of the ethyl(2-hydroxyethyl)phosphinic acid obtained (produced as in Example 8) are at 85° C. dissolved in 400 ml of toluene and admixed with 888 g (12 mol) of butanol. At a reaction temperature of about 100° C., the water formed is removed by azeotropic distillation to leave 500 g (86% of theory) of butyl ethyl(2-hydroxyethyl)phosphinate purified by distillation at reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 1 h

Procedure:
(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) (100 mg, 0.25 mmol) is added to THF (0.5 ml) at 0° C. Sodium triacetoxyborohydride (111 mg, 0.50 mmol) is then added. The mixture is stirred for 1 h then stirred at room temperature overnight. Water (5 ml) is added and then extracted with toluene. Organic phase dried (MgSO4) and concentrated in vacuo to give (R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as for Example 23, Method 1.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]=O)[CH2:15][CH2:14]1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:20][CH2:19][CH:16]2[CH2:17][CH2:18][S:13][CH2:14][CH2:15]2)=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CCC1CCSCC1
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCC2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
0.44 ml of 4-tert-butylbenzylamine (2.5 mmol) and 541 mg (tetrahydro-thiopyran-4-yl)-acetaldehyde (3.75 mmol) were dissolved in 7.5 ml methanol and stirred for 30 min at rt and then refluxed for 2.5 h. After cooling down to rt, 114 mg (3 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was refluxed for 2¾ h. After cooling down to rt, the reaction mixture was treated with 5 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; EtOAc/heptane 1:2 then EtOAc) to give 632 mg light yellow viscous oil (87%). MS (ISP) 292.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([O:13][CH2:14][P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH2:1]([O:8][CH2:9][C@H:10]([O:13][CH2:14][P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OP(=O)(CO[C@H](CI)COCc1ccccc1)OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)OP(=O)(CO[C@H](C)COCc1ccccc1)OC(C)C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
(S)-1-(Benzyloxy)-2-[(diisopropylphosphono)methoxy]-3-iodopropane (11.1 g, 23.5 mmol) was mixed with triethylamine (2.85 g, 28.2 mmol) in 15 mL of methanol. To this solution, 10% palladium on carbon (2.0 g) was added under nitrogen atmosphere. The reaction was performed in a Parr apparatus at a hydrogen pressure of 40 psi. After 3 hours, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (methylene chloride:acetone=1:0 to 5:1) to give 7.91 g (98%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]=O.[CH3:15][C:16]1[C:20](=[O:21])[O:19][CH2:18][C:17]=1[N:22]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:23]1=[O:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[C:3]([CH2:12][CH2:13][N:29]2[CH2:30][CH2:31][C:24]3([C:23](=[O:32])[N:22]([C:17]4[CH2:18][O:19][C:20](=[O:21])[C:16]=4[CH3:15])[CH2:26][CH2:25]3)[CH2:27][CH2:28]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11]
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Reactant: Cc1c(CC=O)ccc2c1COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(N2CCC3(CCN(CCc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (I-3) (100 mg, crude) and 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-16) (145 mg, 0.58 mmol) in THF (5 mL) was stirred at rt for 2 hours and then NaBH(OAc)3 (167 mg, 0.79 mmol) was added to the mixture, which was further stirred at 50° C. for 3 hours. After quenching with saturated NH4Cl aq, the mixture was extracted with EtOAc and organic layer was dried over Na2SO4. Solvent was removed under reduced pressure and the residue was purified by prep-TLC (EtOAc/MeOH: 1/1) and prep-HPLC to give the title product. MS (ESI) m/z: 425 (M+H+); 1H NMR (400 MHz, MeOD): δ 7.69 (d, J=7.6 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 5.38 (s, 2H), 5.27-5.25 (m, 2H), 4.20-4.14 (m, 2H), 3.83-3.80 (m, 1H), 3.68-3.66 (m, 1H), 3.42-3.38 (m, 2H), 3.33-3.23 (m, 4H), 2.41 (s, 3H), 2.39-2.30 (m, 2H), 2.24-2.17 (m, 2H), 2.10-2.03 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:12]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2cc(F)c(F)cc2NC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CNc2cc(F)c(F)cc2N(CC(F)(F)F)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 200 mg of ((S)-7,8-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 7 ml of tetrahydrofurane was cooled to −78° C. under an argon atmosphere. Thereafter, the solution was treated with 0.62 ml of lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofurane), stirred for 30 min at −78° C., then warmed to room temperature before 0.13 ml of 2,2,2-trifluoroethyl trifluoromethanesulphonate were added to the reaction mixture. After stirring overnight in a sealed flask, another 0.05 ml of 2,2,2-trifluoroethyl trifluoromethanesulphonate were added and stirring continued for 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure and the residue was directly submitted to chromatography on a Si—NH2 phase using a gradient of heptane/ethyl acetate=100/0 to 60/30 as the eluent. There were obtained 193 mg (77% of theory) of the title compound as a white foam; MS 418 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[F:7][C:8]([F:18])([F:17])[O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]([F:7])([F:17])[F:18])=[CH:11][CH:12]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromoacetic acid methyl ester (8 ml, 84.2 mmol) was added to a mixture of 4-(trifluoromethoxy)phenol (10 g, 56.1 mmol) and potassium carbonate (11.6 g, 84.2 mmol) in N,N-Dimethylformamide (50 ml) and stirred at room temperature overnight. The reaction mixture was poured into water and neutralized with a 1 N hydrochloric acid aqueous solution, followed by extraction with diethylether. The result was concentrated and used for the subsequent reaction.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][N:7]=1)=O)C.[BH4-].[Na+]>C1COCC1.CO>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:13]=[CH:12][C:11]([C:9]2[O:8][N:7]=[C:6]([CH2:4][OH:3])[CH:10]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(-c2ccc(C(F)(F)F)cc2)on1
Yield: 98.2 %

Procedure:
A solution of 13A (14.1 g, 49.4 mmol) in 3:1 THF/MeOH, was treated with NaBH4 (5.6 g, 148 mmol) at ambient temperature. The reaction was then stired for 3H, followed by concentrating in vacuo to about 50 mL, quenching with 2 M HCl, extract 1×150 mL EtOAC, dry (Na2SO4) and concentrate in vacuo to give 11.8 g of the title compound pure enough for subsequent use. MS m/z 244 (M+1).
Reaction SMILES: C(OC([NH:8][C:9]1([C:18]([OH:20])=[O:19])[CH2:16][CH:15]2[NH:17][CH:11]([CH2:12][O:13][CH2:14]2)[CH2:10]1)=O)(C)(C)C.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@H:29]1[C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:33]([CH2:40]Br)[NH:32][C:31]([C:42]2[S:43][CH:44]=[CH:45][N:46]=2)=[N:30]1>>[NH2:8][C:9]1([C:18]([OH:20])=[O:19])[CH2:10][CH:11]2[N:17]([CH2:40][C:33]3[NH:32][C:31]([C:42]4[S:43][CH:44]=[CH:45][N:46]=4)=[N:30][C@@H:29]([C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[Br:21])[C:34]=3[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:15]([CH2:14][O:13][CH2:12]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC2COCC(C1)N2
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2C3COCC2CC(N)(C(=O)O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Yield: 22.6 %

Procedure:
The title compound was prepared in analogy to Example 133 by using 7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid 139a (49 mg) and ethyl (4R)-6-(bromomethyl)-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 70a (55 mg). 15 mg of the title compound was isolated.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][C:18](=[O:20])[O:17][N:16]=2)=[CH:11][CH:10]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:6][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:19][C:18](=[O:20])[O:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: O=c1[nH]c(-c2ccc([N+](=O)[O-])cc2)no1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2noc(=O)[nH]2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
6.5 g (29 mmol, 4 eq.) of tin(II) chloride dihydrate were added to a solution of 1.5 g (7.2 mmol) of 3-(4-nitrophenyl)-1,2,4-oxadiazol-5(4H)-one in 75 ml of ethanol, and the mixture was stirred at 70° C. for 1 h. The reaction mixture was poured into ice-water, and sodium bicarbonate was added carefully until a pH of 8 had been reached. The mixture was filtered through a filter layer and the residue was washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The residue was stirred with dichloromethane and methanol, treated in an ultrasonic bath for 10 min and then filtered. The filtrate was concentrated under reduced pressure and dried. Yield: 1.4 g (quant.)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:4][N:3]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cn1
Yield: 46.5 %

Procedure:
To a mixture of the amidine of Step 1 (9.8 g, 33.9 mmol) and sodium bicarbonate (5.7 g, 67.8 mmol) in isopropanol (700 ml), 3-bromo-1,1,1-trifluoroacetone (5.3 ml, 50.8 mmol) was added. After heating at 80°-85° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude material (25.7 g) was chromatographed (silica gel, ethyl acetate/acetone, 98/2) to give 2-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (6.3 g, 46%) as a white solid: Anal. Calc'd. for C17H16N3SO3F3 : C, 50.55, H, 4.12, N, 10.40. Found: C, 50.51, H, 3.91, N, 10.25.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.Br[CH2:10][CH2:11]Cl.[H-].[Na+].Cl>CS(C)=O.O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2([C:7]#[N:8])[CH2:11][CH2:10]2)=[CH:2]1
Reactant: N#CCc1ccsc1
Reactant: ClCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccsc2)CC1

Procedure:
A solution of thiophene-3-acetonitrile (30 g) and 1-bromo-2-chloroethane (40.8 ml) in dimethyl sulphoxide (120 ml) was added slowly dropwise to a well stirred suspension of sodium hydride (60% dispersion in mineral oil; 38.8 g) in dimethyl sulphoxide (800 ml) at 30°-35° C. The solution was stirred at ambient temperature for 21 hours then water (100 ml) was carefully added followed by hydrochloric acid (2M; 100 ml). The mixture was extracted with ether (6×80 ml) and the combined extracts washed with water (2×100 ml) then brine and then dried over magnesium sulphate. The solvent was removed in vacuo and the residue washed with petroleum ether (bp 60°-80° C.) before distillation under reduced pressure which gave 1-(3-thienyl)cyclopropanecarbonitrile as an oil (26.3 g), bp 82°-86° C./2 mbar.