Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@@H:51]([C:53]([F:56])([F:55])[F:54])[CH2:52][N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@@H:51]([C:53]([F:54])([F:56])[F:55])[CH2:52][N:44]2[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CC[C@@H](C(F)(F)F)CN3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,8R,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (12 mg, 0.022 mmol) and Intermediate 61 (5.0 mg, 0.019 mmol) to give a white solid (6.5 mg, 43% yield). Anal. Calcd. for C43H51F3N4O5S m/z 792.7. found: 793.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.44-7.04 (m, 11H), 6.96 (dd, J=17.4, 10.3 Hz, 3H), 5.34-5.13 (m, 2H), 4.89 (d, J=63.4 Hz, 3H), 4.47 (dd, J=13.3, 4.2 Hz, 2H), 3.95 (s, 2H), 3.79 (s, 3H), 3.46 (d, J=42.0 Hz, 2H), 3.05 (s, 2H), 2.98-2.66 (m, 5H), 2.64-2.21 (m, 4H), 2.19-1.87 (m, 4H), 1.87-1.37 (m, 8H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([NH:24][C:25]([CH:27]4[CH2:29][CH2:28]4)=[O:26])[N:23]=3)[CH:20]=2)[CH:9]=1)(C)(C)C.COC1C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([N:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a mixture of tert-butyl[3-({2-[(cyclopropylcarbonyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}oxy)phenyl]carbamate (1.79 g, 4.39 mmol) and methoxybenzene (0.5 mL) was added trifluoroacetic acid (8.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and 5% aqueous sodium hydrogen carbonate solution (200 mL) was added to the residue. The obtained precipitate was collected by filtration, and washed with water, diisopropyl ether and hexane to give the title compound (1.13 g, 83%) as a pale-yellow powder. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O1CCCC1.F[C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][CH:35]=1>CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([O:17][C:30]3[CH:35]=[N:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[CH2:16][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(F)(F)F)nc1
Reactant: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(O[C@@H]2C[C@H]3CN(Cc4ccccc4)CCN3C2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 19D, 0.103 g, 0.443 mmol) in dimethyl sulfoxide (4 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.665 mL, 0.665 mmol), and the resulting suspension was stirred at room temperature for 5 minutes. 5-Fluoro-2-(trifluoromethyl)pyridine (0.137 g, 0.829 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel using a solvent gradient of 0-95% ethyl acetate in hexane gave the titled compound. MS (APCI) m/z 378.4 (M+H)+.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:20][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:22][CH:21]=1)#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: N#CNC(=NCc1ccc(C(F)(F)F)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Methyl N-cyano-2 pyridinecarboximidate (0.30 g, 1.9 mmol) was dissolved in methanol (10 ml), 4-(trifluoromethyl)benzylamine (0.36 g, 2.1 mmol) was added, and the resulting mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether to give the title compound (0.47 g, 1.5 mmol, yield: 84%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[C:10](=[N:16][OH:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1CN(Cc2ccccc2)CC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1CN(Cc2ccccc2)CC1=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
A solution of 31.7 g (0.168 mole) of 1-benzyl-4-methyl-3-pyrrolidone [prepared as described in Step (4) above] dissolved in 200 ml of ethanol was added dropwise to a solution of 59.4 g (0.79 mole) of hydroxylamine hydrochloride dissolved in 200 ml of water over a period of 1 hour, whilst keeping the temperature at 20° to 25° C. 62.1 g (0.45 mole) of potassium carbonate were then added, and the mixture was stirred at room temperature overnight, after which it was diluted with 100 ml of water. The aqueous solution was extracted with chloroform, and the chloroform extract was washed with water, dried and concentrated by evaporation under reduced pressure, to give 36.9 g of 1-benzyl-3-(hydroxyimino)-4-methylpyrrolidine as brown crystals.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.CON(C)[C:11]([C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)=[O:12]>C1COCC1>[CH3:7][N:6]1[C:2]([C:11]([C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)=[O:12])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1csc(C)n1
Reactant: Cn1cncc1Br
Solvent: C1CCOC1
Product: Cc1nc(C(=O)c2cncn2C)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 5-bromo-1-methyl-1H-imidazole (345 mg, 2.14 mmol) was added THF (8 mL) and the solution was cooled to 0° C. To this clear homogeneous solution was added isopropylmagnesium chloride-LiCl complex (1.3 M, 2.0 mL, 2.6 mmol) which resulted in a white suspension. The reaction was stirred at 0° C. for 30 min, then a THF (2 mL) solution of N-methoxy-N,2-dimethylthiazole-4-carboxamide (250 mg, 1.34 mmol, Intermediate 38, step a) was introduced and the mixture became more viscous and was allowed to warm to room temperature. After 3 hours the mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (20-40% EtOAc-DCM increasing gradient to 5% MeOH-DCM) provided the title compound as an off-white solid.
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([CH3:18])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[O:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[N+:15]([C:14]1[C:9]([O:8][CH3:7])=[C:10]([C:29]2[O:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=2)[CH:11]=[C:12]([CH3:18])[CH:13]=1)([O-:17])=[O:16]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cc(C)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2ccc(C(=O)O)o2)cc(C)cc1[N+](=O)[O-]
Yield: 27.7 %

Procedure:
To a solution of the solvent mixture of 30 mL of 1,4-dioxane and 15 mL of water was added 2-(2-methoxy-5-methyl-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 24a (3.1 g, 7.5 mmol) followed by 5-bromofuran-2-carboxylic acid (1.3 g, 6.8 mmol), tetrakis(triphenylphosphine)palladium (0.43 g, 0.4 mmol) and sodium carbonate (1.6 g, 15.1 mmol). The reaction mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled and filtered. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The resulting residue was diluted with 50 mL of water and adjusted to pH 3 with concentrated hydrochloric acid and filtered. The filter cake was washed with ethyl acetate and dried to obtain the title compound 5-(3-nitro-2-methoxy-5-methyl-phenyl)-furan-2-carboxylic acid 46a (522 mg, 29%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:15](O)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18].CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[C:15]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:23]
Reactant: CC(C)(C)OC(=O)NCCOCCN
Reactant: O=C(O)c1ccccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
tert-Butyl 2-(2-aminoethoxy)ethylcarbamate was then taken up in CH2Cl2 (20 mL) along with salicylic acid (576 mg, 4.17 mmol) and EDCI (905 mg. 4.72 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(2-hydroxybenzamido)ethoxy)ethylcarbamate (450 mg, 33%). Mass, calculated for C16H24N2O5: 324.17; found: [M+H]+=325.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][CH:10]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11](OCC)=[O:12].Cl>ClCCl>[CH3:9][C:10]1[C:11](=[O:12])[C:7]2[C:2](=[CH:3][CH:4]=[C:5]([CH3:8])[CH:6]=2)[NH:1][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=O)C(C)C(=O)OCC
Reactant: Cc1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccc(C)cc2c(=O)c1C
Yield: 71.2 %

Procedure:
A mixture of p-toluidine (10 g) and diethyl 2-methyl-3-oxosuccinate (18.9 g) in dichloromethane (50 ml) was refluxed for 2 days. The reaction mixture was poured onto 0.5N hydrochloric acid (200 ml) and extracted with dichloromethane. The organic layer was washed with water, 0.5N sodium hydroxide solution and brine, dried over magnesium sulfate, and concentrated. The obtained residue was added to heated diphenyl (80 g) and the mixture was refluxed for 15 minutes. The reaction mixture was allowed to stand at ambient temperature, and the resulting precipitates were collected by filtration to give ethyl 1,4-dihydro-3,6-dimethyl-4-oxoquinoline-2-carboxylate (16.3 g).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](Cl)=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[CH:25]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:15][C:16]2[CH:37]=[CH:36][CH:35]=[C:18]([O:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]5[CH2:33][CH2:34]5)=[O:31])[N:28]=4)[CH:25]=3)[CH:17]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)nn5c4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (5.0 mL) was added N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.485 mmol) produced in Example B2(vii), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained oil was triturated with ethyl acetate, toluene and diisopropyl ether to give the title compound (175 mg, 63%) as a colorless powder.
Reaction SMILES: Cl.CO[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:15])[CH3:14]>C(O)C.O>[CH2:13]([NH:15][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])[CH3:14]
Reactant: COc1ccncc1[N+](=O)[O-]
Reactant: CCN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 96 %

Procedure:
4Methoxy-3-nitropyridine hydrochloride (11.2 g, 58.9 mmol) in ethanol (75 ml) was treated with a 70% solution of ethylamine in water (64 ml) and heated under reflux for 2 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue dissolved in ethyl acetate and water. The mixture was extracted (×3) with ethyl acetate, washed with water and saturated aqueous sodium chloride solution before drying over magnesium sulfate. Evaporation of the solvent afforded the title compound (11.7 g, 96%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][C@H:9]1[CH2:20][CH3:21])(C)(C)C.P(=O)(O)(O)O>O1CCCC1>[NH2:7][C@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][C@H:9]1[CH2:20][CH3:21]
Reactant: CC[C@@H]1Oc2ccccc2NC(=O)[C@@H]1NC(=O)OC(C)(C)C
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Product: CC[C@@H]1Oc2ccccc2NC(=O)[C@@H]1N

Procedure:
The title compound was prepared in quantitative yield by reaction of 590 mg (1.93 mmol) ((6S,7R)-6-ethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester with 2.86 g (29 mmol) ortho phosphoric acid in 6 ml tetrahydrofurane, MS m/e (%): 207.1 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][N:7]1[C:13](=[O:14])[C@@H:12]2[C@H:8]1[C@@H:9](OC(N1C=CN=C1)=S)[CH2:10][N:11]2[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][N:7]1[C:13](=[O:14])[C@@H:12]2[C@H:8]1[CH2:9][CH2:10][N:11]2[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@@H](OC(=S)n2ccnc2)CN3C(=O)OCc2ccccc2)cc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)[C@@H]3[C@H]2CCN3C(=O)OCc2ccccc2)cc1OC

Procedure:
200 g (0.38 mol) of benzyl (1S,4S,5S)-6-(3,4-dimethoxybenzyl)-7-oxo-4-[[(1-imidazolyl)thiocarbonyl]oxy]-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate were heated to 80° C. in 4.2liters of toluene. A solution of 213 ml (0.8 mol) of tributyltin hydride and 6.9 g (0.04 mol) of AIBN in 320 ml of toluene were added dropwise thereto while stirring. After completion of the dropwise addition the mixture was stirred at this temperature for a further 45 minutes before the solvent was removed under reduced pressure. There remained behind a yellowish turbid oil which was chromatographed over 1100 g of silica gel (0.063-0.2 mm particle size with 1) ethyl acetate: hexane 1:10; 2) ethyl acetate: hexane 2:1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](Br)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[O:36][C:35]([Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])=[N:34][CH:33]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:32]4[O:36][C:35]([Si:37]([CH:41]([CH3:43])[CH3:42])([CH:44]([CH3:46])[CH3:45])[CH:38]([CH3:39])[CH3:40])=[N:34][CH:33]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Product: CC(C)[Si](c1ncc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)(C)C)CC2)O3)o1)(C(C)C)C(C)C

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole following a procedure analogous to that described for Intermediate 15. LC (method 6): tR=1.62 min; Mass spectrum (ESI+): m/z=527 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:26])[CH2:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:3][CH2:2]1.[CH3:27][C:28](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:29]>>[C:28]([O:26][CH:11]([CH2:12][C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:21])([F:20])[C:16]([F:19])([F:17])[F:18])[CH2:10][O:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:29])[CH3:27]
Reactant: OC(COCCN1CCOCC1)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CC(=O)OC(COCCN1CCOCC1)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 10 h
Yield: 273.5 %

Procedure:
To 40.7 g of 1-(2-morpholinoethoxy)-4,4,5,5,6,6,7,7,7-nonafluoro-2-heptanol was added 11.2 g of acetic anhyride. The mixture was stirred at 50° C. for 10 hours, followed by conventional aqueous work-up and purification by silica gel column chromatography. There was obtained 42.7 g of 1-(2-morpholinoethoxy)-4,4,5,5,6,6,7,7,7-nonafluoro-2-heptyl acetate (yield 95%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[N:22]1([C:2]2[N:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCCC2)cc1C(F)(F)F

Procedure:
A mixture of 2.5 g (10.43 mmol) of methyl 6-chloro-4-trifluoromethylnicotinate, of 2.88 g (20.87 mmol) of potassium carbonate and of 2.61 ml (31.3 mmol) of pyrrolidine in 90 ml of dimethylformamide is heated at 100° C. for 3 hours. The reaction mixture is subsequently concentrated under reduced pressure and then taken up in 100 ml of water. A precipitate is recovered by filtration and is washed with 150 ml of water. After drying under reduced pressure, 2.5 g of the expected product are isolated.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[N:25]=[C:24]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Reactant: Clc1ccnc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.31) (10.89 g, 30 mmol) and commercially available 2,4-dichlorpyrimidine (4.47 g, 30 mmol) according to the general procedure IVc protocol b. Obtained as an off-white solid (7.2 g, 68%). MS (ISP) 350.2 [(M+H)+] and 352 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13](=[O:39])[O:14][C:15]2[C:20]([C:21]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=1)=[CH:19][CH:18]=[C:17]([O:37]C)[CH:16]=2.[OH-].[Na+]>CC(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13](=[O:39])[O:14][C:15]2[C:20]([C:21]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[CH:25][CH:24]=1)=[CH:19][CH:18]=[C:17]([OH:37])[CH:16]=2
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3Cl)c(=O)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(C(F)(F)F)cc1Cl
Temperature: 130 °C
Reaction time: 15 h

Procedure:
3-(2-Chloro-4-trifluoromethylphenyl)-7-methoxy-4-(4-(2-pyrrolidin-1-yl-ethoxy)-benzyl)-chromen-2-one (330 mg, 0.59 mmol) was dissolved in AcOH (2.4 mL)-48% aq HBr (2.4 mL). The mixture was stirred at 130° C. for 15 h. After cooling the mixture to r.t., it was poured onto EtOAc/aq NaHCO3. 1M aq NaOH was then added to bring the pH to 8. The layers were separated and the aqueous layer was back-extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The residue was purified using flash chromatography (silica gel, 5:1 CH2Cl2-MeOH) to provide the title compound as a yellow foam showing: IR (KBr) v=3670-2140, 1709, 1611, 1569, 1511, 1367, 1323, 1247, 1172, 1133, 1081, 1067, 1044, 1012 cm−1. 1H NMR (400 MHz, CD3OD) δ 7.81 (d, 1H, J=1.5 Hz), 7.61 (dd, 1H, J=1.5, 8.0 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.48 (d, 1H, J=8.0 Hz), 6.93 (d, 2H, J=8.5 Hz), 6.79 (d, 2H), J=8.5 Hz), 6.76 (d, 1H, J=2.5 Hz), 6.73 (dd, 1H, J=2.5, 8.8 Hz), 4.09 (t, 2H, J=5.5 Hz), 4.05 (d, 1H, J=15.5 Hz), 3.80 (d, 1H, J=15.5 Hz), 3.04 (t, 2H, J=5.5 Hz), 2.86-2.78 (m, 4H), 1.92-1.82 (m, 4H). HRMS (ESI) calcd for C29H25ClF3NO4 (M+H)+: 544.1502; found 544.1504.