Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](Cl)=[O:12])(=[O:3])[CH3:2].[F:14][C:15]1[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([F:24])[C:16]=1[CH:17]=[O:18].C(N(CC)CC)C.C(Cl)Cl>O>[C:1]([O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:23][C:21]1[CH:22]=[C:15]([F:14])[C:16]([CH:17]=[O:18])=[C:19]([F:24])[CH:20]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: O=Cc1c(F)cc(O)cc1F
Reactant: CC(=O)OC[C@@H]1CCCN1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC[C@@H]1CCCN1C(=O)Oc1cc(F)c(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.1 %

Procedure:
To a 250 mL dry round bottom flask were added (S)-(1-(chlorocarbonyl)pyrrolidin-2-yl)methyl acetate (6.79 g, 33.0 mmol), 2,6-difluoro-4-hydroxybenzaldehyde (4.74 g, 30 mmol), triethylamine (5.40 mL, 39.0 mmol) and anhydrous CH2Cl2 (40 mL). The resulting mixture was stirred at room temperature for 2 days, then water (80 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (80 mL×2). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give (S)-3,5-difluoro-4-formylphenyl 2-(acetoxymethyl)pyrrolidine-1-carboxylate (4.92 g) as a colorless oil. Yield: 46%. 1H NMR (CDCl3, 300 MHz, mixture of two isomers): 8=10.28 (s, 1H), 6.97 (t, J=11.4 Hz, 2H), 4.33-4.12 (m, 3H), 3.65-3.55 (m, 2H), 2.10-2.01 (m, 7H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): δ=183.5, 170.7 (d, J=7.3 Hz), 163.6 (dd, J=262.5, 8.6 Hz), 157.0, 150.8 (d, J=14.6 Hz), 112.6, 106.2 (d, J=25.0 Hz), 64.4, 63.8, 56.8, 56.4, 47.4, 47.3, 28.7, 27.8, 23.8, 22.9, 20.8.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][CH:3]=1.[CH2:11]([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>C1(C)C=CC=CC=1>[CH2:11]([S:18][C:6](=[S:20])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(O)c1ccc(F)cc1
Reactant: SCc1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C(=S)SCc2ccccc2)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 4-fluorobenzoic acid (1.40 g), benzyl mercaptan (1.24 g) and phosphorus pentasulfide (4.44 g) in toluene (40 ml) was refluxed for 12 h. A dark red color was developed immediately after heating. After the reaction was complete (as monitored by GC-MS), it was cooled to room temperature and purified by a column chromatography packed with neutral alumina, eluting with benzene. Removal of the solvent by distillation gave the single compound, benzyl-4-fluorodithiobenzoate (1.86 g, 71%). It was further characterized by 1H and 13C-NMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([S:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:6]([Cl:20])[C:5]=1SCC[Si](C)(C)C.[NH4+:29].[Cl-].C1COCC1>CCO.CO.[Zn]>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([S:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:6]([Cl:20])[C:5]=1[NH2:29]
Reactant: [NH4+]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(SCC[Si](C)(C)C)c(Cl)c1SCC[Si](C)(C)C
Agent: [Cl-]
Agent: [Zn]
Solvent: CO
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(SCC[Si](C)(C)C)c(Cl)c1N
Reaction time: 1 h
Yield: 78 %

Procedure:
3-chloro-5-nitro-2,4-bis-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester) in a ratio 74:36 (NMR integrals), are suspended in 16 ml of EtOH and 20 ml of MeOH. Then, 16 ml of a saturated NH4Cl aqueous solution are added followed by 20 ml of THF. 788 mg (0.012 mol, 4.4 eq.) of dust powdered zinc are added and the reaction is stirred during 1 h 30. 50 ml of a saturated NH4Cl aqueous solution are added to the mixture and the product is extracted with CH2Cl2 (3 times). The regrouped organic phases are dried with Na2SO4, filtered and evaporated. A column chromatography purification on silica gel with hexanes and EtOAc gave 680 mg (78%) of pure 2,5-diamino-3-chloro-4-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester; 1H-NMR (CDCl3, 300 MHz): 0.02 (s, 9H), 0.78-0.89 (m, 2H), 2.83-2.91 (m, 2H), 3.88 (s, 3H), 7.33 (d, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl[CH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([O:8][CH2:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccsc1CCl
Reactant: Nc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccsc1COc1cccnc1N
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 2-amino-3-hydroxypyridine (15.18 g) in N,N-dimethylformamide (150 ml) was added portionwise a 60% dispersion of sodium hydride in mineral oil (6.06 g) with ice-cooling and stirring over a period of 10 minutes. After being stirred at 0°-5° C. for 30 minutes and then at ambient temperature for 1 hour, a solution of 2-chloromethyl-3-methylthiophene (23.9 g) in N,N-dimethylformamide (10 ml) was added dropwise to the reaction mixture. The mixture was stirred at ambient temperature for 20 hours and poured into water. The resulting precipitate was collected by filtration and dissolved in methylene chloride. The solution was treated with activated charcoal and evaporated in vacuo. The residue was crystallized from diethyl ether to give 2-amino-3-(3-methyl-2-thienylmethoxy)pyridine (23.6 g).
Reaction SMILES: C([O:8][C:9]([C@:11]12[CH2:18][CH2:17][C@@:14]([CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)=[O:10])C1C=CC=CC=1>C(O)C.O.[Pd]>[CH3:24][O:23][C:21]([CH2:20][CH2:19][C:14]12[CH2:15][CH2:16][C:11]([C:9]([OH:10])=[O:8])([CH2:18][CH2:17]1)[CH2:12][CH2:13]2)=[O:22]
Reactant: COC(=O)C=C[C@]12CC[C@@](C(=O)OCc3ccccc3)(CC1)CC2
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COC(=O)CCC12CCC(C(=O)O)(CC1)CC2

Procedure:
4-(2-Methoxycarbony-vinyl)-bicyclo[2.2.2]octane-1-carboxylic acid benzyl ester (XX, Example 95, 35 g, 106.6 mmol) is dissolved in ethyl alcohol/water (9/1, 300 ml) and is placed in a Porter pressure bottle. Palladium on carbon (10%, 5 g) is added and the mixture is hydrogenated (65 psi) for 48 hr. The reaction mixture is filtered through a pad of celite and the combined filtrates were concentrated to give the title compound, NMR (400 MHz, CDCl3) δ 3.58, 2.18, 1.74, 1.44 and 1.38.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1.NN.O>CCO.CN(C=O)C>[Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: NCc1ccc(Cl)nc1Cl
Yield: 81.9 %

Procedure:
In a mixture of 50 ml EtOH and 20 ml DMF was dissolved 3.1 g (0.01 mole) of N-(2,6-dichloro-3-pyridylmethyl)phthalimide under heating, followed by addition of 0.75 g (0.015 mole) of H2NNH2.H2O under reflux. After 1 hour of refluxing, EtOH and DMF were distilled off. To the residue were added 10 ml of concentrated hydrochloric acid and 5 ml of water, and the mixture was refluxed for 30 minutes. The resulting crystals were filtered off and the filtrate was neutralized with NaHCO3 and extracted with CH2Cl2 (30 ml×3). The extract was dried over MgSO4 and the solvent was distilled off to give 1.45 g of the title compound as a yellow oil.
Reaction SMILES: CC[O-].[Na+].[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CCO>[F:5][C:6]([F:15])([F:16])[C:7]([CH:8]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:14]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CCOC(=O)CCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC(C(=O)OCC)C(=O)C(F)(F)F
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
To a solution of NaOEt (0.217 mol) in EtOH (prepared from 5.0 g of Na and 220 mL of EtOH) was added ethyl trifluoroacetoacetate (40.0 g, 0.217 mol). After 10 min, ethyl 3-bromopropionate (35.0 g, 0.194 mol) was added and the mixture was heated under reflux for 24 h. The reaction mixture was concentrated, taken up in ether, and washed with water. The ether layers were dried (MgSO4) and concentrated to give 50 g of a yellow oil. Distillation (100°-110° C./25 min) gave 14.0 g (23%) of product as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:26])[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C1C=CC=CC=1.[BH4-].[Na+]>CO>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:26])=[CH:17][CH:18]=1)=[O:21]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(OCC(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 3.43 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 4.5 g of methyl 4-(2-oxopropoxy)benzoate (prepared as described in European Patent Publication No. 6735), 100 ml of benzene, 100 ml of absolute methanol and 2.7 g of sodium borohydride were used, to give the title compound as crystals, melting at 99°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](SC)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][CH:33]([NH2:35])[CH3:34].[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])[CH3:42])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:35][CH:33]([CH3:34])[CH3:32])=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CNCCCN(C)C
Reactant: CC(C)N
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N(C)CCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid by following the procedures in Example 19 using 2-propanamine for the amide formation and N,N,N′-trimethyl-1,3-propanediamine for the displacement reaction (88%). LC-MS (ES) m/z 549 (M+H)+; 1H-NMR(MeOD) δ 1.27 (d, 6H), 1.60 (m, 1H), 1.80 (m, 1H), 2.06 (m, 1H), 2.22 (m, 6H), 2.33 (m, 4H), 2.86 (m, 1H), 3.19 (m, 2H), 3.40 (m, 1H), 3.70 (m, 1H), 4.30 (m, 1H), 6.00 (m, 1H), 6.33 (d, 1H), 7.10 (t, 2H), 7.30 (m, 2H), 7.42 (d, 1H), 7.48 (m, 1H), 7.66 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH2:14]OS(C)(=O)=O)=[O:10])[CH2:4][CH2:3]1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(#N)C>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH2:14][N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:10])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H]1C(=O)N[C@H]1CC[C@H](C)CC1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CC#N
Product: C[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3cccc(Cl)c3)CC2)CC1

Procedure:
Reflux a solution of methane sulfonic acid 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 11d) (30.0 mg, 0.1 mmol), 1-(3-chloro-phenyl)-piperazine hydrochloride (29.0 mg, 0.13 mmol) triethylamine (0.05 mL, 0.4 mmol) in acetonitrile (5 ml) for 15 h. Concentrate the reaction mixture under vacuum and chromatograph the residue over silica gel to obtain 11.3 mg (28%) of solid, LC/MS, m/z=390 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[N:7][CH:8]=1)[CH3:2].BrN1C(=[O:17])CCC1=O.[OH-].[Na+].[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>C(O)(C)(C)C.O.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:17])[CH2:10][O:21][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1ccc(CC)cn1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
To a flask fitted with an overhead stirrer, a thermometer and a condensor was added a solution of 12 Kg (90.22 mole) 5-ethyl-2-vinyl-pyridine dissolved in a mixture of 45 lit. tert-butanol and 135 lit. water at 25° C., followed by addition of 19.26 Kg (108.25 mole) N-bromosuccinimide and reaction mixture was stirred for 1.5 hr. 135 lit. aqueous 2N NaOH solution was added to the reaction mixture and stirring was continued for further 45 min. Progress of reaction was monitored by TLC and after completion of reaction, product was extracted with 120 lit. methylene chloride. Layers were separated, organic layer was washed with 72 lit. brine solution, dried (magnesium sulfate) and concentrated under reduced pressure. The residue mass obtained was added into a stirred mixture of 15.96 Kg (130.8 mole) 4-hydroxy benzaldehyde dissolved in 130 lit. toluene and 5.23 Kg (1307 mole) NaOH dissolved in 120 lit. water. To this was added 2.21 Kg PEG 4000 and stirred for 17 hr. at 78° C. Subsequent work-up gave 20.538 Kg (84%) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde. m.p. 82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:23]>CC(C)=O>[Cl:23][C:9]1[C:10]2[C:5](=[C:4]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]ncc2c1Cc1ccncc1
Solvent: CC(C)=O
Product: COc1ccc2c(Cl)nncc2c1Cc1ccncc1
Temperature: 85 °C
Yield: 62 %

Procedure:
A suspension under N2 of 6-methoxy-5-pyridin-4-ylmethyl-2H-phthalazin-1-one (2.26 g,), prepared as described in example 141, in POCl3 (40 ml) was heated for 3 hours at 85° C., then dried. The residue was taken up in a saturated NaHCO3 solution up to alkalinity, then filtered and extracted with ethyl acetate. The solid was dissolved in a CH2Cl2/CH3OH/ethyl acetate mixture, dried over Na2SO4 and filtered. The solution was joined to the previous organic phase and dried to give a residue which was taken up in acetone and filtered yielding 1.5 g of the title compound (yield: 62%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]2)=[C:4]([F:15])[CH:3]=1.[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][C:11]3([O:18][CH2:17][CH2:16][O:14]3)[CH2:10]2)=[C:4]([F:15])[CH:3]=1
Reactant: O=C1CCC(c2cc(F)c(Br)cc2F)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1cc(C2CCC3(C2)OCCO3)c(F)cc1Br
Yield: 88.4 %

Procedure:
A solution of 27.5 g (0.1 mol) of 3-(4-bromo-2,5-difluorophenyl)cyclopentanone, 18.6 g (0.3 mol) of ethylene glycol, 1 g of p-toluenesulfonic acid and 500 ml of toluene was heated at reflux with a Dean-Stark trap for 18 hours. The cooled solution was washed with 5% sodium bicarbonate solution (2×250 ml), dried (MgSO4), and evaporated in vacuo to give 28.2 g of the title compound which was used without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.FC(F)(F)C(O)=O.[O:72]=[C:73]1[CH:77]=[CH:76][C:75](=[O:78])[N:74]1[CH2:79][CH2:80][CH2:81][C:82]([NH:84][CH2:85][CH2:86][NH:87][CH3:88])=[O:83].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:72]=[C:73]1[CH:77]=[CH:76][C:75](=[O:78])[N:74]1[CH2:79][CH2:80][CH2:81][C:82]([NH:84][CH2:85][CH2:86][N:87]([CH3:88])[C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:83]
Reactant: CNCCNC(=O)CCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)N(C)CCNC(=O)CCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6 mg (7 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 61) were combined with 3.1 mg (9 μmol) of 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-[2-(methylamino)ethyl]butanamide trifluoroacetate, 10.1 mg (27 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 5 μl of N,N-diisopropylethylamine in 2 ml of DMF, and the mixture was stirred at RT for 4 h. Then the solvent was removed under reduced pressure and the remaining residue was purified by means of preparative HPLC. The corresponding fractions were concentrated and, by lyophilization from dioxane, 1 mg (13.4% of theory) of the title compound were obtained.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([C:11]1[C:12](O)=[N:13][C:14]([CH2:17][CH3:18])=[N:15][CH:16]=1)=[O:10])[CH3:7]>C(N(CC)CC)C>[CH2:6]([O:8][C:9]([C:11]1[C:12]([Cl:3])=[N:13][C:14]([CH2:17][CH3:18])=[N:15][CH:16]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1cnc(CC)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(CC)nc1Cl
Temperature: 0 °C

Procedure:
7.5 ml of triethylamine were slowly introduced into 300 ml of phosphorous oxychloride cooled to 0° C., then were added 30 g of 5-ethoxycarbonyl 4-hydroxy 2-ethyl pyrimidine (VII) prepared in the preceding stage and the suspension was brought up to 40° C. under nitrogen scavenging. After dissolution, the phosphorous oxychloride was evaporated and the residue diluted in a mixture of water and chloroform. This was decanted, the chloroform phase was twice washed with water, dried on sodium sulfate and the solvent evaporated. The raw product obtained, after checking the purity by thin layer chromatography, was reacted in the following stage 3.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][N:8]=[C:7]1SC)=[O:5].[NH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>COCCOCCOC.O>[N:18]1([N:17]2[C:2]3[C:3](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4](=[O:5])[N:6]3[CH2:10][CH2:9][N:8]=[C:7]23)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CSC1=NCCN1C(=O)c1ccccc1F
Reactant: NN1CCCCC1
Solvent: COCCOCCOC
Solvent: O
Product: O=C1c2ccccc2N(N2CCCCC2)C2=NCCN12
Yield: 71 %

Procedure:
A solution of 10.0 g (42.0 mmoles) of the product of Example 1 and 25 ml of 1-aminopiperidine in 50 ml of 2-methoxyethyl ether (diglyme) was heated at reflux for 15 hours. The solution as diluted while hot with about 5 ml of water and allowed to cool. The resulting white needles were collected, washed with ethanol, and air-dried to give 8.10 g of 2,10-dihydro-10-(1-piperidinyl)imidazo[2,1-b]quinazolin-5(3H)-one. Melting point 229°-231° C. Total yield 71%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]([OH:20])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Si]([O:51][CH2:52][C@H:53]([C:55]1[CH:56]=[N:57][C:58]([CH3:61])=[N:59][CH:60]=1)[NH2:54])(C(C)(C)C)(C)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:51][CH2:52][C@@H:53]([NH:54][C:18]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=1)=[O:20])[C:55]1[CH:56]=[N:57][C:58]([CH3:61])=[N:59][CH:60]=1
Reactant: Cc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](CO)c3cnc(C)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (35 mg, 0.12 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol), 1-hydroxybenzotriazole hydrate (18 mg, 0.12 mmol), and CH2Cl2 (3 mL) were added (S)-2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethanamine (48 mg, 0.18 mmol) (WO 2008/130481) and N,N-diisopropylethylamine (42 μL, 0.24 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was dissolved in MeOH (5 mL) and concentrated HCl solution (0.5 mL) was added. The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% MeCN-water[10 mM Et2NH]) to afford a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH:6]=[C:7]([Cl:11])[CH:8]=2)[NH:3]1.[OH-].[Na+].[O:22]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:6][C:7]([Cl:11])=[CH:8][C:9]=1[CH2:10][C:2]([OH:22])=[O:1]
Reactant: C1COCCO1
Reactant: O=C1Cc2cc(Cl)cc(Oc3ccccc3Cl)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cc(Cl)cc1Oc1ccccc1Cl

Procedure:
A mixture of 2-oxo-5-chloro-7-(2-chlorophenoxy)indoline (2.0 g.), sodium hydroxide (0.50 g.), dioxane (20 ml.) and water (30 ml.) was refluxed under heating for 23 hours. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in water and filtered. The filtrate was washed with diethyl ether, and diethyl ether was added to the aqueous layer and adjusted to pH 5 with 1N-sulfuric acid. The diethyl ether layer was separated, washed with water, dried over magnesium sulfate and then evaporated. The residue was recrystallized from ethanol to give crystals of 2-[2-amino-3-(2-chlorophenoxy)-5-chlorophenyl]acetic acid (0.725 g.).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15]/[CH:16]=[CH:17]/[OH:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[CH:17]=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C/C=C/O)cc1OC1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(/C=C/C=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 0.12 g (0.48 mmol) of 3-cyclopentoxy-4-methoxyphenyl-E-propenyl alcohol in 20 mL of dry methylene chloride was added 0.5 g (6.1 mmol) of activated manganese dioxide in one portion. After stirring the brown suspension at room temperature for 6 hours, the mixture was filtered over Celite 545, eluted with two, 30 mL portions of chloroform, and concentrated. Crystallization of the crude product from hexane provided the desired, analytically pure product upon drying in vacuo.