Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:15]([CH2:16][C:17]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][C:13]([CH2:24]O)=[CH:12][N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46].O>C1(C)C=CC=CC=1>[Br:46][CH2:24][C:13]1[CH:14]=[C:15]([CH2:16][C:17]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[N:11][CH:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2CC2(C#N)CCCC2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)c(-c2ncc(CBr)cc2CC2(C#N)CCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
To a solution of 1-((2-(2-fluoro-5-methoxyphenyl)-5-(hydroxymethyl)pyridin-3-yl)methyl)cyclopentanecarbonitrile (353 mg) and triphenylphosphine (410 mg) in toluene (10 mL) was added carbon tetrabromide (512 mg), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (339 mg) as white crystals.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]=[CH:34][N:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[N:32]=1)(=[O:3])[CH3:2].[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]=[CH:34][N:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[N:32]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cn1cnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cn1cnc(/C=C2\CNCCC2SC(C)=O)n1
Yield: 54 %

Procedure:
Following a procedure similar to that described in Example 132-(f), (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,4-triazol-3-yl]methylidene}-1-(triphenylmethyl)piperidine obtained in Example 166-(c) was treated with trifluoroacetic acid in dichloromethane and the crude product was purified by silica gel chromatography using dichloromethane and methanol (20:1 to 10:1) as an eluent to afford the title compound (860 mg, yield: 54%) as a yellow amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:29]=[C:14]3[N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH:16]=[N:17][C:18](Cl)=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].[F:31][C:32]1[C:40]([OH:41])=[CH:39][CH:38]=[C:37]2[C:33]=1[CH:34]=[C:35]([CH3:42])[NH:36]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:29]=[C:14]3[N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH:16]=[N:17][C:18]([O:41][C:40]4[C:32]([F:31])=[C:33]5[C:37](=[CH:38][CH:39]=4)[NH:36][C:35]([CH3:42])=[CH:34]5)=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncn(Cc4ccc(OC)cc4)c-3n2)cc1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc3c(Oc4ccc5[nH]c(C)cc5c4F)ncn(Cc4ccc(OC)cc4)c-3n2)cc1
Temperature: 95 °C

Procedure:
A mixture of 3.96 g (9.4 mMol) of 4-[4-chloro-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid ethyl ester, 2.14 g (13 mMol) of 4-fluoro-5-hydroxy-2-methyl-1H-indole (preparation see WO 00/47212; Ex. 237) and 2.44 (17.7 mMol) of K2CO3 in 90 ml of DMF is heated for 9 h at 95° C. The reaction mixture is concentrated in vacuuo, the residue dissolved in EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2, EtOAc/hexane 1:1) gives the title compound; TLC (EtOAc/hexane 1:1) Rf=0.24; MS-ES+: (M+H)+=551.
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14])([O-:10])=[O:9]>O1CCCC1.O>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1)=[O:14])([O-:10])=[O:9]
Reactant: Nc1nnn[nH]1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 10.3 g of 5-aminotetrazole monohydrate in 300 ml of tetrahydrofuran and 15 ml of water was added 9.3 g of 2-nitrobenzoyl chloride. The solution was allowed to stand for 30 minutes before it was diluted with 200 ml of water and stored in a refrigerator for 72 hours. The solid which formed was separated by filtration to give 2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 272°-273° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Br)=[C:10]([O:14][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:16][CH3:17].C([O-])([O-])=[O:19].[Ca+2]>COCCOC.O>[Br:1][C:2]1[C:11]([CH2:12][OH:19])=[C:10]([O:14][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:16][CH3:17]
Reactant: O=C([O-])[O-]
Reactant: COc1c(Br)c(CBr)c(OC)c2ccccc12
Agent: [Ca+2]
Solvent: O
Solvent: COCCOC
Product: COc1c(Br)c(CO)c(OC)c2ccccc12
Temperature: 25 °C
Yield: 104.4 %

Procedure:
Following a modified procedure of Smith et al.,25 dibromide 36 (1.73 g, 4.80 mmol) was dissolved in 1,2-dimethoxyethane (50.0 mL), and then added to CaCO3 (2.50 g, 25.0 mmol) in H2O (50.0 mL) at room temperature. The reaction was heated under reflux for TIME and then cooled to room temperature. The reaction was extracted with EtOAc (75.0 mL), and the organic layers are washed with brine. The organic layer was dried over MgSO4 and filtered. The resulting pink solid was then purified by flash column chromatography (1:3 EtOAc:hexanes) to provide 37 (1.49 g, 5.01 mmol, 105%) as a pink solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.O.[C:18](=O)(O)[O-].[Na+]>CO>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:18])=[O:6]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(O)c(I)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(O)c(I)c1

Procedure:
A solution of 3-iodo-4-hydroxybenzoic acid (28.76 g, 0.11 mol) and sulphuric acid (6.6 ml) in methanol (160 ml) is refluxed for 6 h. 300 ml of water are added and the mixture is basified with sodium bicarbonate until neutral. It is extracted with ethyl ether (600 ml). The organic phase is washed with twice 400 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on the column of silica (10% ethyl acetate, 90% CH2Cl2).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].[OH-].[Na+]>O>[C:5]1([N:4]([CH2:13][CH2:12][C:11]([OH:15])=[O:14])[CH2:1][CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCNc1ccccc1
Reactant: C=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(CCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of N-propyl aniline (5.0 g), acrylic acid (5.1 ml) and water (7 ml) was stirred for 2 hours under reflux. After cooling to room temperature, the aqueous solution was adjusted to pH 11 with 5N aqueous sodium hydroxide and washed four times with ether. The aqueous layer was acidified to pH 3 with concentrated hydrochloric acid and extracted three times with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 7.2 g (94%) of the objective compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:31]=[C:30]([N:32]4[CH2:37][CH2:36][N:35]([CH2:38][C:39]5[CH2:44][CH2:43][C:42]([CH3:46])([CH3:45])[CH2:41][C:40]=5[C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=5)[CH2:34][CH2:33]4)[CH:29]=[CH:28][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([C:26]#[N:27])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[O:54]1CCCC1.OO.[OH-].[Na+]>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:31]=[C:30]([N:32]4[CH2:33][CH2:34][N:35]([CH2:38][C:39]5[CH2:44][CH2:43][C:42]([CH3:46])([CH3:45])[CH2:41][C:40]=5[C:47]5[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=5)[CH2:36][CH2:37]4)[CH:29]=[CH:28][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([C:26](=[O:54])[NH2:27])[CH:20]=3)(=[O:17])=[O:18])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(N)c(C#N)c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(N)c(C(N)=O)c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 45 °C

Procedure:
To a solution of EXAMPLE 70B (90 mg) in ethanol (2 mL) was added tetrahydrofuran (2 mL), hydrogen peroxide (30%, 1 mL) and 1M sodium hydroxide solution (0.48 mL), followed by an additional 2 mL of tetrahydrofuran. The reaction was heated to 45° C. for 30 minutes, cooled, and then quenched with 5% HCl solution and extracted twice with dichloromethane. The extracts were combined and concentrated to obtain the product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].Cl.[CH3:13][C:14]1[C:15]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[CH:17][N:16]=3)[CH2:22][CH2:23]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(Cl)c3)CC2)c(C)c1
Yield: 99.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 69 and using 4-bromo-3-chlorobenzoic acid (989 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (956 mg) described in Preparation Example 64, the title compound (1.7 g) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([O:17][CH2:18][CH3:19])[CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].C(N(CC)CC)C.C([SiH](CC)CC)C>C(Cl)Cl.[Pd](Cl)Cl>[CH2:18]([O:17][C@H:16]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:11][C:4]1[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=[C:6]([CH2:9][CH3:10])[N:5]=1)[CH3:19]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)cnc1CC
Agent: Cl[Pd]Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)cnc1CC
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate (14.55 g, 36.5 mmole) in CH2Cl2 (0.1 M, 365 ml) under N2 was added palladium chloride (1.29 g, 7.24 mmole) and triethyl amine (7.61 mL, 1.5 eq.). Triethylsilane (8.74 mL, 1.5 eq.) was added dropwise over 15 min. After one hour, an additional 8.74 mL of triethylsilane were added dropwise. After 2 additional hours, the reaction mixture was filtered through celite. Trifluoroacetic acid (8 mL) was added and the reaction mixture was stirred for 30 minutes, basified to pH 10 with 2 N aqueous NaOH and extracted with CH2Cl2 (3×300 ml), dried with MgSO4, filtered and concentrated. Vacuum chromatography was run on a 1 L frit funnel with 5-15% MeOH/CH2Cl2 with 0.5% NH4OH gave 8.75 g (91%) of N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine as an oil. IR (liq.) 3438, 2971, 2935, 2874, 2452, 1580, 1546, 1498, 1465, 1448, 1395, 1343, 1164, 1124, 1078 cm−1 HRMS (ESI) calcd for C14H24N4O+H1 265.2028. found 265.2026. [α]25D=−45° (c 1.02, chloroform).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[ClH:31]>O>[ClH:31].[C:24]1([CH2:23][NH:30][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)Nc1ccc(/C=C\COCCCCCCBr)cc1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: O
Product: CS(=O)(=O)Nc1ccc(/C=C\COCCCCCCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Z)-N-[4-[3-[(6-Bromohexyl)oxy]-1-propenyl]phenyl]methanesulphonamide (2.0 g) was added to benzylamine (6 ml) at 125°, under nitrogen. The reaction mixture was stirred at 125° for 3 h, cooled to room temperature and added to 2N hydrochloric acid (50 ml) and water (20 ml). The resultant white solid was collected by filtration, washed in turn with 2N hydrochloric acid, water and ether then dried in vacuo at 50° to give the title compound as a white powder (1.0 g) m.p. 133°-134°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16]#[N:17])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[C:25]([O:28][CH2:29][CH2:30]Br)(=[O:27])[CH3:26].CN(C)C=O>O>[C:25]([O:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16]#[N:17])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCCBr
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(O)cc23)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCOc1ccc2nc(CC(C)C)c(C#N)c(-c3ccc(C)cc3)c2c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
A mixture of 6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (5.0 g, 15.8 mmol), 2-bromoethyl acetate (3.2 g, 19 mmol) and N,N-dimethylformamide (20 ml) was stirred at 50° C. for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous-magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether and filtered to give 2-{[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}ethyl acetate (5.0 g, yield 79%) as crystals.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:12]([Mg]Cl)[CH:13]([CH3:15])[CH3:14].S(=O)(=O)(O)O>O1CCCC1.O>[CH3:12][CH:13]([CH3:15])/[CH:14]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(C)C[Mg]Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)/C=C/c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
4-Carboxybenzaldehyde (1.0 g, 6.66 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to 0° C. To the mixture was added isobutylmagnesium chloride (16 mL, 32 mmol, 2.0 M solution in THF). The reaction mixture was warmed to room temperature and stirred for 2 hours. The solution was acidified with 50% sulfuric acid in water and the THF was removed under vacuum. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to give the desired compound (950 mg) as grey powder.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH2:11])[CH2:4][CH2:3]1.F[C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:11][C:21]2[CH:22]=[N:23][CH:24]=[CH:16][C:17]=2[C:18]([OH:20])=[O:19])[CH2:4][CH2:3]1
Reactant: NCc1cccc(OCC2CC2)c1
Reactant: O=C(O)c1ccncc1F
Agent: Cl
Product: O=C(O)c1ccncc1NCc1cccc(OCC2CC2)c1
Yield: 7 %

Procedure:
The title compound was prepared in 7% yield from 3-cyclopropylmethoxy-benzylamine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 8.07 (s, 1H), 7.79 (d, 1H, J=5.0 Hz), 7.57 (d, 1H, J=5.0 Hz), 7.23 (t, 1H, J=8.0 Hz), 6.89-6.95 (m, 2H), 6.79 (d, 1H, J=7.6 Hz), 4.49 (s, 2H), 3.78 (d, 2H, J=6.9 Hz), 1.15-1.21 (m, 1H), 0.51-0.57 (m, 2H), 0.27-0.32 (m, 2H). [M+H] calc'd for C17H18N2O3, 299. Found 299.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2nccc(Cl)c2cc1OC
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 69.5 %

Procedure:
A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60° C. and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 77° C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 to 7° C. and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26% NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25° C., and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to −20 to −25° C. and held for 2.5 hours resulting in solid precipitate, which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25° C. under nitrogen to afford the title compound (35.6 kg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([P:16]([OH:28])([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7].[C:29](OC(=O)C)(=[O:31])C>C(O)=O>[CH:29]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]([P:16]([OH:28])([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:17])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])=[O:31]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCC(C(=O)N1CCC[C@H]1C(=O)O)P(=O)(O)CCCCc1ccccc1
Solvent: O=CO
Product: O=CNCCCC(C(=O)N1CCC[C@H]1C(=O)O)P(=O)(O)CCCCc1ccccc1
Reaction time: 3 h

Procedure:
A solution of 1 g (2.44 mmol) of (±)-1-[5-amino-2-[hydroxy-(4-phenylbutyl)phosphinyl]-1-oxopentyl]-L-proline (prepared as described in Example 1) in a mixture of 5 ml of acetic anhydride and 15 ml of 90% formic acid is kept at room temperature for 3 hours, then evaporated to give the title product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[CH3:13].[H-].[Na+].[Cl:16][CH2:17][CH2:18][CH2:19]I>CN(C=O)C>[Cl:16][CH2:17][CH2:18][CH2:19][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:13])=[C:2]([F:1])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:12]
Reactant: Cc1cc2c(cc1F)NC(=O)CC2
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1F)N(CCCCl)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
A reaction flask was charged with 7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one (97KK40) (0.102 g, 0.57 mmol) in dry DMF (5 mL) under an argon atmosphere. Washed NaH (0.015 g, 0.63 mmol) was added and the mixture was stirred at rt for 1 h. Then 1-chloro-3-iodopropane (0.104 g, 0.51 mmol) dissolved in DMF (1 mL) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into Et2O. The combined organic layers were washed with aqueous 4% MgSO4, dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; DCM/n-heptane 2:1, DCM, MeOH/DCM 1:10) to give the title compound (112KK01) (0.050 g, 38%). 1H NMR (CDCl3) δ 6.95-6.93 (m, 1H), 6.73 (d, J=11.5 Hz, 1H), 4.03-4.00 (m, 2H), 3.59 (t, J=6.5 Hz, CH2), 2.83-2.79 (m, 2H), 2.62-2.58 (m, 2H), 2.20 (d, J=1.8 Hz, CH3), 2.13-2.07 (m, 2H).
Reaction SMILES: [CH:1]1([S:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.O>O1CCCC1>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:8]([S:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:9]#[N:10]
Reactant: COc1ccc(C(C#N)SC2CCCCC2)cc1OC
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C#N)(CCCCCBr)SC2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.57 g of product from Example 82 in 180 ml of anhydrous tetrahydrofuran, under argon, is added 1.3 g of 50% sodium hydride in oil. The mixture is stirred at room temperature for 1 hour; followed by the addition of 10.6 ml of 1,5-dibromopentane and the stirring is continued for 4 hours at room temperature. The reaction mixture is poured into 450 ml of water and extracted with diethyl ether. The organic layer is washed with saturated sodium chloride, dried, filtered and concentrated in vacuo to give 23 g of a crude oil. The oil is purified by chromatography (silica gel: hexane to 10% ethyl acetate/hexane) to give 8.9 g of the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][CH2:15][C:16]#[CH:17]>C(#N)C.O>[CH2:17]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:16][C:15]#[CH:14]
Reactant: C#CCCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCCN1CCCCC1
Temperature: 80 °C
Yield: 40.5 %

Procedure:
A mixture of piperidine (T1, 2.90 g, 34.0 mmol), potassium carbonate (3.00 g, 21.7 mmol), and 4-bromobut-1-yne (5.00 g, 37.6 mmol) in anhydrous acetonitrile (60 mL) was heated to 80° C. under nitrogen for 20 h. After this time, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound T2 as light brown oil (1.89 g, 40%): MS (M+H) 138.
Reaction SMILES: [OH:1][C:2]([CH:18]([CH3:20])[CH3:19])([CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([O:6]C)=[O:5].[CH3:21]O.Cl>O>[CH3:21][CH:3]([C:2]([OH:1])([CH:18]([CH3:20])[CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([OH:6])=[O:5]
Reactant: CO
Reactant: COC(=O)CC(O)(CCCCc1ccccc1)C(C)C
Agent: Cl
Solvent: O
Product: CC(C)C(O)(CCCCc1ccccc1)C(C)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 0.88 g (3.17 mmol) of the methyl 3-hydroxy-3-isopropyl-7-phenylheptanoate in 30 mL of 1:1:1-THF:MeOH:H2O is added 1.08 g (25.36 mmol, 8 eq) of LiOH monohydrate and this is stirred at 25° C. for 1 month. This mixture is then acidified to pH=6 with 1 N HCl and then partitioned between ethyl acetate and water. The organics are dried (Na2SO4) and concentrated in vacuo to afford methyl 3-hydroxy-3-isopropyl-7-phenylheptanoic acid in the form of a pale yellow crystalline solid. (0.59 g, 70%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 0.98(d, 6H), 1.35(m, 1H), 1.55(m, 5H), 2.1(m, 1H), 2.35(t, 1H), 2.6(t, 2H), 3.88(m, 1H), 6.08(bs, 2H), 7.15(m, 3H), 7.25(m, 2H).