Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:16]([CH:17]=1)[C:15](=[O:18])[C:14]1[C:9](=[CH:10][CH:11]=[C:12]([C:19]([OH:21])=[O:20])[CH:13]=1)[N:8]=2)[CH3:3].Br.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31]Br)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][O:20][C:19]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]2[CH:6]=[CH:5][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:17][N:16]2[C:15]3=[O:18])=[O:21])[CH:24]=1
Reactant: BrCCCc1cccnc1
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cc3c(=O)n2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc2nc3ccc(C(=O)OCCCc4cccnc4)cc3c(=O)n2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A suspension of 0.60 g of 8-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid, 0.63 g of 3-(3-pyridyl)propyl bromide hydrobromide and 0.62 g of potassium carbonate in 50 ml of dimethylformamide was stirred at a bath temperature of 70° C. for three hours. The mixture was diluted with dichloromethane and washed successively with water, 10% sodium hydroxide, and water and was dried over K2CO3. The residue obtained after evaporation afforded 0.40 g of 8-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid 3-(3-pyridyl)propyl ester, mp 111°-112° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][N:22]=1.C([Sn](CCCC)(CCCC)[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)CCC>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:33](/[C:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][N:22]=1)=[CH:34]\[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccnc(Br)c1
Reactant: CCCC[Sn](C=Cc1ccccc1)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ccnc(/C=C/c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
Under inert atmosphere (Ar) a mixture of palladium-(II)-acetate (0.117 mg, 0.5 mmol) and triphenylphosphine (0.248 g, 0.9 mmol) in DMF (13 ml) was stirred for 30 min at rt. 2-Bromo-pyridin-4-ylamine (0.90 g, 5.2 mmol) (H. J. den Hertog, C. R. Kolder and W. P. Combe, Rec. Trav. Chim., 1951, 70, 591) was added followed by tributyl-styryl-stannane (3.93 g, 10 mmol). After heating at 130° C. for 15 min the solvent was evaporated and the residue partitioned between AcOEt and 3N HCl. The aqueous phase was neutralized with 6N NaOH and extracted with AcOEt. The organic phase was dried with Na2SO4, concentrated and chromatographed (SiO2 with CH2Cl2/CH3OH/NH4OH=140/10/1) to give the title compound (0.40 g, 39%) as a colorless solid. Mp. 164-165° C. (AcOEt), MS: 196 (M+).
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7].C([O-])=O.[NH4+:20]>[Pd].O.CO>[CH3:1][Si:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:20])[CH2:10][CH2:9]1)=[O:7]
Reactant: [NH4+]
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(=O)CC1
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOC(=O)N1CCC(N)CC1
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A slurry of 10% palladium on carbon (200 mg) in water was added to 4-oxo-piperidine-1-carboxylic acid-2-trimethylsilanyl-ethyl ester (2.42 g, 10 mmol) in 100 mL of methanol. Ammonium formate (6.0 g, 95 mmol) in water was added dropwise, and the mixture stirred vigorously overnight. The mixture was filtered and the filtrate concentrated in vacuo to leave the crude product. Chromatography (elution with methanol-dichloromethane) provided 0.98 g of product.
Reaction SMILES: Cl[C:2]([F:27])([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>C(O)C.[Pd]>[F:27][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NC(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Yield: 89.8 %

Procedure:
This compound was prepared as described in Example 54: 2.7 g (0.006 mol) of product of Example 60, 0.65 g (0.006 mol) of triethylamine and 0.12 g of Pd/C (10%) in 30 ml of ethanol were reacted affording an oil residue which was kugelrohr distilled at 80 Pa, pot temperature 104° C., to give 2.07 g (89.8%) of product as a white solid; mp 53°-55° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[Cl-].[Li+].[CH2:14]1[O:17][CH:15]1[CH3:16].S(=O)(=O)(O)O>CN(C)C=O>[OH:17][CH:15]([CH3:14])[CH2:16][N:7]1[C:3]([CH2:1][CH3:2])([CH2:10][CH3:11])[C:4](=[O:9])[N:5]([CH2:14][CH:15]([OH:17])[CH3:16])[C:6]1=[O:8]
Reactant: CCC1(CC)NC(=O)NC1=O
Reactant: CC1CO1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC1(CC)C(=O)N(CC(C)O)C(=O)N1CC(C)O
Reaction time: 5 h

Procedure:
A solution of 125.0 g of 5,5-diethylhydantoin (0.8 mol), 300.0 g of dimethylformamide and 2.00 g of lithium chloride is stirred at 52° C. 128 g of propene oxide (2.2 mols) are added dropwise over the course of 21/2 hours. Stirring is then continued for 5 hours at 85°-90° C. The reaction mixture is adjusted to pH = 7 with 2-3 drops of 25% strength sulphuric acid, and is filtered. The clear solution is concentrated on a rotational evaporator at 80° C. bath temperature, under a waterpump vacuum, and is subsequently treated under a high vacuum (0.2 mm Hg) at 80° C. until constant weight is reached.
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)=O.[CH2:25]([NH2:27])[CH3:26]>C1(C)C=CC=CC=1>[CH2:25]([NH:27][CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH3:26]
Reactant: CCN
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: Cc1ccccc1
Product: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
A solution of (2RS)-2-(2-cyano-10-phenothiazinyl)-propyl methanesulphonate (50 g) and ethylamine (100 cc) in toluene (600 cc) is heated for 24 hours to a temperature in the region of 105° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with distilled water (250 cc) and the mixture is extracted successively with ethyl acetate (500 cc and 250 cc). The combined organic phases are extracted with N aqueous hydrochloric acid solution (2×500 cc). The aqueous phases are alkalinized with caustic soda (d=1.33) to pH 13 and extracted successively with ethyl acetate (500 cc and 250 cc). The combined organic phases are washed with saturated aqueous sodium chloride solution (250 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[(2RS)-1-Ethylamino-2-propyl]-2-phenothiazinecarbonitrile (30.4 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)([OH:15])[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)([OH:15])[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(O)(c2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(O)(c4cccc(F)c4)C3)CC2)cc1
Yield: 66.9 %

Procedure:
The title compound (D161) (64.7 mg) was prepared according to the experimental procedure described in Description 146 (reaction time 1 h) starting from 5-chloro-2-(3-(3-fluorophenyl)-3-hydroxyazetidin-1-yl)nicotinic acid (D111) (63 mg, 0.195 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (44.4 mg, 0.195 mmol).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C([Li])CCC.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH4+].[Cl-]>C1COCC1.ClCCl>[CH:7]1[C:8]2[C:3](=[C:2]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Brc1cccc2cnccc12
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
The product from Example 57A (11.80 g, 56.6 mmol) in THF (200 mL) at −78° C. was treated with n-butyllithium (30 mL, 75.0 mmol, 2.5M in hexanes) dropwise. After 30 minutes, the mixture was treated with diethyl oxalate (25.0 mL, 184 mmol). After 20 minutes, the solution was allowed to warm to room temperature and was treated with saturated NH4Cl (150 mL). The mixture was conentrated under reduced pressure. The residue was treated with dichloromethane (100 mL) filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (20% ethyl acetate/hexanes) to provide the title compound as light brown oil (4.57 g, 35%). MS (ESI+) m/z 248 (100), 230 (M+H)+, (ESI−) m/z 200 (M-Et)−; 1H NMR (DMSO-d6, 300 MHz) rotomers δ 1.26 (t, J 7.1, 0.6H), 1.37 (t, J 7.1, 2.4H), 4.21 (q, J 7.1, 0.4H), 4.47 (q, J 7.1, 1.6H), 7.89 (t, J 7.5, 1H), 8.41 (dd, J 1.0, 7.5, 1H), 8.57 (d, J 8.1, 1H), 8.64 (d, J 5.7, 1H), 8.73 (d, J 6.3, 1H), 9.50 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[CH:29][C:28](=[O:32])[N:27]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:38]CCl>Cl.C(OCC)C>[ClH:38].[CH:33]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[C:30]([CH3:31])=[CH:29][C:28]2=[O:32])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: ClCCl
Reactant: Cc1cc(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCNCC4)cn3)ncc12
Reaction time: 48 h
Yield: 90.9 %

Procedure:
4-[6-(8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.093 g, 0.184 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl in diethyl ether (2 mL) was added and the resulting mixture was stirred for 2 days. Additional 2 N HCl was added and stirring was continued for 16 hours. The solvent was removed to give 8-cyclopentyl-5-methyl-2-(5-piperazin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.080 g, 90.9%). 1H NMR δ (400 MHz, DMSO-d6) 9.92 (s, 2H), 8.85 (s, 1H), 8.02 (d, J=2.9 Hz, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.78 (d, J=9.3 Hz, 1H), 6.33 (s, 1H), 5.79 (m, 1H), 3.40 (m, 4H), 3.22 (m, 4H), 2.39 (s, 3H), 2.20 (m, 2H), 1.91 (m, 2H), 1.74 (m, 2H), 1.56 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH:14]=[C:13]([C:15]([CH3:39])=[CH:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[H][H]>FC(F)(F)C(O)=O.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH2:14][CH:13]([CH:15]([CH3:39])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH2:12][NH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=C(C)c2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CC(C)C2CNc3nc(NC(C)=O)nc(O)c3C2)cc1)C(=O)OCC
Yield: 23 %

Procedure:
A solution of 84.4 mg of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)prop-1-enyl]benzoyl)-L-glutamate in 30 mL of trifluoroacetic acid was hydrogenated at 55 psi of hydrogen in the presence of 0.42 g of 5% Pd/C at room temperature for 24 hours. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The resulting residue was taken up in chloroform and was extracted with a saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was then subjected to thin layer chromatography using a 5% methanol:chloroform mixture as the eluent. After elution of a first fraction, there was obtained 19.6 mg of the title compound, NMR (CDCl3 250 MHz), d 1.20-1.33(m, overlapping methyls, 9H), 2.45-3.36(m, 15H), 4.11(q, 2H, J=7.14 Hz), 4.23(q, 2H, J=7.10 Hz), 4.89(m, 1H), 5.44(brs, 1H), 7.24(d, 2H, J=7.54 Hz), 7.72(d, 2H, J=7.54 Hz), 9.77(brs, 1H), 11.26(brs, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])=[CH:20][C:19]=1[F:27]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and B-(4-chloro-3-fluorophenyl)-boronic acid, (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 96%, 348.0058 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:8]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Cc1ccc(F)cc1N
Agent: Br
Product: Cc1ccc(F)cc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 61.7 %

Procedure:
5-fluoro-2-methylaniline (102 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(5-fluoro-2-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (56 mg, 61%) as a white solid. Mass Spectrum: M+H+ 454. NMR Spectrum (DMSOd6): 1.60 (d, 3H), 2.20 (s, 3H), 2.69 (bs, 3H), 2.93 (bs, 3H), 3.53-3.65 (m, 4H), 3.72-3.80 (m, 4H), 5.08-5.18 (m, 1H), 5.62 (s, 1H), 5.73 (d, 1H), 6.52 (d, 1H), 6.92 (dd, 1H), 7.18 (dd, 1H), 7.58 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][CH2:14][CH2:15][OH:16]>>[C:1]([O:16][CH2:15][CH2:14][CH2:13][C:12]([F:11])=[C:17]([F:19])[F:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCCCC(F)=C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)OCCCC(F)=C(F)F
Temperature: 25 °C
Yield: 90.6 %

Procedure:
31.7 g (0.41 mol) of acetyl chloride were added dropwise to a two-necked round-bottomed flask, cooled in an ice bath, equipped with a reflux condenser (connected to a trap comprising potassium carbonate) and comprising 50.1 g (0.36 mol) of 4,5,5-trifluoropent-4-en-1-ol. The reactivity of the two reactants was monitored by sparging of the trap by HCl. After the completion of the addition, the mixture was stirred at ambient temperature until HCl was no longer being evolved (approximately 4 hours). After distillation, 59.3 g (0.326 mol) of 4,5,5-trifluoro-4-pentenyl acetate (colourless liquid) were obtained. Boiling point=56-58° C./21 mmHg. (Yield=91%.).
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@H:25]([CH2:54][C:55]3[CH:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[C:58]([NH2:65])=[C:57]([Cl:66])[CH:56]=3)[C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][CH:37]([N:40](C(OCC)=O)[CH2:41][C:42]([O:44][C:45](C)(C)[CH3:46])=[O:43])[CH2:36][CH2:35]4)[CH2:30][CH2:29]3)=[O:27])=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:67]=[CH:68][CH:69]=[CH:70][C:11]=2[NH:10]1>C(Cl)Cl>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:54][C:55]3[CH:60]=[C:59]([C:61]([F:62])([F:63])[F:64])[C:58]([NH2:65])=[C:57]([Cl:66])[CH:56]=3)[C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:36][CH2:35]4)[CH2:32][CH2:33]3)=[O:27])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:67]=[CH:68][CH:69]=[CH:70][C:11]=2[NH:10]1
Reactant: CCOC(=O)N(CC(=O)OC(C)(C)C)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CNC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
0.5 mL TFA were added to a solution of 330 mg (0.36 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(tert-butoxycarbonyl-ethoxycarbonyl-methylamino)-1,4′-bipiperidinyl-1′-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 5 mL DCM cooled to 0° C. and the reaction mixture was stirred overnight at RT. It was evaporated down i. vac. and the residue was purified by HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([NH:16][CH:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[CH3:31][Mg+].[Br-]>O1CCCC1>[OH:1][CH:2]([CH3:31])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([NH:16][CH:17]4[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](CC=O)CC4)CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C[C@H]1CCc2sc3ncnc(NC4CCC(NC(=O)OC(C)(C)C)CC4)c3c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
For the preparation of the starting material compound 26.3, see Example 26. Into a 50-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-(4-[[(3R)-3-(2-oxoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino]cyclohexyl)carbamate (250 mg, 0.58 mmol, 1.00 equiv) in freshly distilled tetrahydrofuran (10 mL) at 0° C. under nitrogen. The CH3MgBr (1.0 M in THF, 2.9 mL, 5.0 equiv) was added at 0° C. via syringe. The resulting solution was stirred for 2 h at 0° C. and quenched with saturated aqueous NH4Cl and extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give the desired racemic tert-butyl N-(4-[[(3R)-3-(2-hydroxypropyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino]cyclohexyl)carbamate (109 mg, 42%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([O:29]CC)=[O:28])=[CH:19][C:18]=2[CH:32]=1>>[Cl:13][C:14]1[C:15]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:25])([F:24])[F:26])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=2[CH:32]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(OC(F)(F)F)cc1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(OC(F)(F)F)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-(trifluoromethoxy)phenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 198.0-199.2° C. 1H NMR (acetone-d6 /300 MHz) 7.91 (s, 1H), 7.73 (s, 1H), 7.43 (d, 2H, J=9.1 Hz), 7.25 (d, 2H, J=9.1 Hz), 6.70 (s, 1H), 5.82 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -59.4 (s, 3F), -79.4 (d, 3F, J=7.2 Hz). ESLRMS m/z 453 (M-H). ESHRMS m/z 452.9950 (M-H, Calc'd 452.9964). Anal. Calc'd for C18H9ClF6O5 : C, 47.55; H, 2.00; Cl, 7.80. Found: C, 47.47; H, 1.89; Cl, 8.02.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][CH2:9][C:10]([N:12]1[CH2:16][C@H:15]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C@H:13]1[C:26]([OH:28])=[O:27])=[O:11]>C(O)=O>[C:18]([NH:17][C@H:15]1[CH2:16][N:12]([C:10](=[O:11])[CH2:9][NH:8][CH:1]=[O:3])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:14]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Solvent: O=CO
Product: O=CNCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.6 %

Procedure:
Acetic anhydride (Acros) (0.32 mL, 3.4 mmol, 10 equivalents) was added dropwise to a solution of (2S4R)1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid (Compound 2, 0.1 g, 0.34 mmol, 1 equivalent) in formic acid (J. T. Baker) (1 mL) at 0° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred an additional 24 hours. The reaction mixture was monitored by TLC and LCMS. An additional amount of acetic anhydride (0.32 mL, 3.4 mmol, 10 equivalents) was added and the reaction mixture stirred for 24 hours at room temperature. Ice-water (1 mL) was added and the volatiles were removed in vacuo to yield an oily crude product that was further purified by HPLC (column: Waters Atlantis 19×150 mm) using 0.1% formic acid in H2O/MeOH 20-40% MeOH over 15 minute gradient to afford 0.031 g (29%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]#[C:12][CH2:13][CH2:14][OH:15]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: COc1ccc(C#CCCO)c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCCCO)c(OC)c1
Yield: 89.7 %

Procedure:
To a solution of 75 (4.2 g, 0.022 mol) in ethanol (approx. 200 mL) was added palladium (5% wet on activated carbon, 1 g). Then the mixture was hydrogenated at 40 psi overnight at room temperature. The mixture was filtered through a pad of silica gel and the solvent was evaporated to give 76 (4.15 g, 97%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ1.59 (m, 4H), 2.55 (m, 2H), 3.79 (s, 6H), 6.43 (m, 2H), 7.00 (m, 1H).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]([C:10]23[CH2:18][CH:14]([NH:15][CH:16]2[CH3:17])[CH2:13][CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1.[BrH:19]>>[BrH:19].[OH:3][C:4]1[CH:5]=[C:6]([C:10]23[CH2:18][CH:14]([NH:15][CH:16]2[CH3:17])[CH2:13][CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C23CCCC(C2)NC3C)c1
Agent: Br
Agent: Cl
Product: CC1NC2CCCC1(c1cccc(O)c1)C2

Procedure:
A mixture of 5.22 g of 1-(3-methoxyphenyl)-7-methyl-6-azabicyclo[3,2,1]octane hydrochloride and 52 ml of 47 % aqueous hydrobromic acid is refluxed for one hour under heating. After cooling, the crystalline precipitate is collected by filtration. The precipitate is recrystallized from a mixture of methanol and ether. 5.48 g of 1-(3-hydroxyphenyl)-7-methyl-6-azabicyclo[3,2,1]octane hydrobromide are obtained. M.p. 282°-284°C.