Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)(=O)OC.[CH2:20]([O:22][C:23](=[O:39])[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:35](=[O:36])[CH2:34][CH2:33][CH2:32][C@@H:31]1[CH:37]=O)[CH3:21]>C1COCC1>[CH2:20]([O:22][C:23](=[O:39])[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:35](=[O:36])[CH2:34][CH2:33][CH2:32][C@@H:31]1/[CH:37]=[CH:9]/[C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH3:21]
Reactant: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)Cc1cccc(Cl)c1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 35 mg, 0.88 mmol) was added to a solution of [3-(3-chlorophenyl)-2-oxopropyl]-phosphonic acid dimethyl ester (221 mg, 0.80 mmol) in THF (2.0 mL) at 0° C. After 1 h at 0° C., [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid ethyl ester (0.88 mmol, crude) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 10 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20% →40% EtOAc/CH2Cl2, gradient) afforded 117 mg (34%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2C(=C[C:11]=1[OH:12])OC(=O)[CH:6]=[C:5]2[C:14]([F:17])([F:16])[F:15].[CH3:18][Mg]Cl.O.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:26](=[CH:22][C:11]=1[OH:12])[O:25][C:24]([CH3:23])([CH3:18])[CH:6]=[C:5]2[C:14]([F:15])([F:16])[F:17]
Reactant: C1CCOC1
Reactant: O=c1cc(C(F)(F)F)c2cc(Cl)c(O)cc2o1
Reactant: C[Mg]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C=C(C(F)(F)F)c2cc(Cl)c(O)cc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 6-chloro-7-hydroxy-4-(trifluoromethyl)-2H-chromen-2-one (1.5 g, 5.68 mmol) in anhydrous THF (25 mL) was added at 0° C. a solution of methyl magnesium chloride in THF (9.48 mL of 3 mol solution). After stirring at 0° C. for 1 h, the reaction was quenched with sat.NH4Cl aq. The organic layer was separated, washed with water, dried over anhydrous Na2SO4 and concentrated to provide the crude product. This was dissolved in toluene (50 mL) and to this was added p-toluenesulfonic acid (40 mg) and the solution was kept at reflux for 1 h with the azeotropic removal of water using Dean-Stark apparatus. The solution washed once with water, dried over anhydrous Na2SO4 and concentrated to give brownish residue which was subjected to purification over silica gel using AcOEt/hexanes to provide the desired product (1.3 g, 83%).
Reaction SMILES: I[C:2]1[C:11]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:22]([C:2]1[C:11]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1)#[N:23]
Reactant: CCC(CC)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1I
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC(CC)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C#N
Temperature: 100 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
Methyl 4-iodo-5-(pentan-3-ylamino)-2-(trifluoromethyl)benzoate (401 mg, 0.966 mmol) was dissolved in DMF (9 mL) and the mixture was sparged with nitrogen for 15 minutes. Zinc cyanide (79 mg, 0.673 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.086 mmol) were added and the mixture was stirred at 100° C. for 15 h. The reaction mixture was cooled to ambient temperature and was filtered through celite. The filter cake was washed with ethyl acetate and the filtrate was washed with 5% lithium chloride (2×). The combined aqueous wash was back-extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, then filtered and concentrated to afford a brown semi-solid which was purified by column chromatography (silica gel, 30-50% dichloromethane in hexanes) to afford methyl 4-cyano-5-(pentan-3-ylamino)-2-(trifluoromethyl)benzoate (262 mg, 0.834 mmol, 86% yield) as colorless crystals. 1H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 6.96 (s, 1H), 4.76 (d, 1H), 3.94 (s, 3H), 3.49-3.38 (m, 1H), 1.75-1.63 (m, 2H), 1.61-1.49 (m, 2H), 0.96 (t, 6H); GCMS for C15H17F3N2O2: 314 (M+).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>C(Cl)(Cl)Cl>[Br:1][CH2:14][C:13]([C:7]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=1)=[O:15]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)CBr)cc1OC
Reaction time: 1.5 h
Yield: 47.6 %

Procedure:
A solution of bromine (30.6 g, 1.2 eg) in chloroform (150 ml) was added dropwise to a solution of 1-(3,4-dimethoxyphenyl)-1-ethanone (28.8 g) in chloroform (50 ml) over a period of 3-5 hr. The mixture was stirred for 1.5 hr. A stream of nitrogen was passed to remove the hydrobromic acid gas. The mixture was diluted with chloroform, washed with water, aqueous sodium bicarbonate and water, dried and evaporated. The crude product (48.3 g) was passed through a silica gel column (1.5 kg) using ethyl acetate-hexane (1:4) and the eluates were evaporated to give 2-bromo-1-(3,4-dimethoxyphenyl)-1-ethanone (19.7 g), mp 87°-90° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[C:5]([O:20][CH3:21])=[CH:4][N:3]=1.[N+:22]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])([O-:24])=[O:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>C(#N)C.O>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[C:5]([O:20][CH3:21])=[CH:4][N:3]=[C:2]([NH:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:19][CH2:18]1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1cnc(Nc2cccc([N+](=O)[O-])c2)nc1-c1cnn(C(CC#N)C2CC2)c1

Procedure:
A solution of a mixture of 3-[4-(2-chloro-5-methoxypyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyclopropylpropanenitrile (from example 320 step 1, 60 mg, 0.0002 mol), m-nitroaniline (40.9 mg, 0.000296 mol), and p-toluenesulfonic acid (29 mg, 0.00017 mol) in dry 1,4-dioxane (1 mL, 0.02 mol) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC at pH 10 to give the desired product as a racemic mixture (free base). LCMS (M+H) 406.2.
Reaction SMILES: [C-:1]#[N:2].[Na+].C([O:6][C:7](=[O:13])[CH2:8][C@H:9]([OH:12])[CH2:10]Cl)C.[C-]#N>C(O)(=O)C>[C:1]([CH2:10][C@@H:9]([OH:12])[CH2:8][C:7]([OH:6])=[O:13])#[N:2]
Reactant: CCOC(=O)C[C@H](O)CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Product: N#CC[C@@H](O)CC(=O)O
Reaction time: 0.02 h

Procedure:
A first feed tank was charged with a 15% (w/w) aqueous solution of sodium cyanide. A second feed tank was charged with an 80% w/w aqueous solution of acetic acid. A third feed tank was charged with (S)-ethyl-4-chloro-3-hydroxybutyrate. The sodium cyanide and acetic acid solutions were mixed at a molar ratio of 21:1 using a plug flow reactor element with a 1.4-second residence time at ambient temperature. The mixture was continuously fed into a two-stage plug flow reactor element into which (S)-ethyl-4-chloro-3-hydroxybutyrate was continuously fed such that the molar ratio of cyanide to substate was 2:1. The two stage reactor element consisted of an initial pre-mixer with a 4.5 second residence time and a secondary mixer with a 72 second residence time, both mixing elements being contained within a heat transfer medium such that the reaction temperature was maintained at between 105° C. and 110° C. The mixture was then continuously quenched using additional 80% acetic acid in a plug flow reactor element with a residence time of 4.0 seconds at ambient temperature. The quench acid flow rate was adjusted to maintain the crude product flow stream at a pH of between 5.0 and 5.5. The crude product was obtained as an aqueous solution, which was subjected to steam distillation to remove contaminants. The aqueous residue was then extracted with dichloromethane and the product (R)-4-cyano-3-hydroxybutyric acid was isolated in 80% chemical yield after solvent evaporation and simple vacuum distillation.
Reaction SMILES: [BrH:1].[CH3:2][C:3]([NH:17]CC(C1C=CC(O)=C(O)C=1Cl)=O)([CH3:16])[CH2:4][NH:5][C:6](=[O:15])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br.CC(N[CH2:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[C:52]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:51]=1Cl)=[O:49])(C)CNC(=O)COC1C=CC=CC=1>>[NH2:17][C:3]([CH3:16])([CH3:2])[CH2:4][NH:5][C:6](=[O:15])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1.[Br:1][CH2:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[C:52]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH:51]=1)=[O:49]
Reactant: CC(C)(CNC(=O)COc1ccccc1)NCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1Cl
Reactant: Br
Reactant: CC(C)(CNC(=O)COc1ccccc1)NCC(=O)c1ccc(O)c(O)c1Cl
Product: CC(C)(N)CNC(=O)COc1ccccc1
Product: O=C(CBr)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
The above acetophenone derivative (A) was itself prepared in 85% yield, as a solid m.p. 141°-143° C. by a similar procedure to that described for the equivalent starting material in Example 11, but from 2-{[1,1-dimethyl-2-(2-phenoxyacetamido)ethyl]amino}-2'-chloro-3',4'-bis(benzyloxy)acetophenone hydrobromide. The latter compound was itself obtained in 40% yield as a solid, m.p. 61°-63° C., from N-(2-amino-2-methylpropyl)-2-phenoxyacetamide and 2-bromo-3',4'-bis(benzyloxy)acetophenone using a procedure similar to that in Example 11.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:13][CH2:12][CH2:11][CH2:10][O:9]1.[Mg].[CH2:15]1[O:27][C:26]2[CH:25]=[C:24]3[C:19]([CH:20]=[C:21]([N+:28]([O-:30])=[O:29])[CH2:22][O:23]3)=[CH:18][C:17]=2[O:16]1.O>C1COCC1.BrCCBr>[CH2:15]1[O:27][C:26]2[CH:25]=[C:24]3[C:19]([CH:20]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[CH:8]4[O:13][CH2:12][CH2:11][CH2:10][O:9]4)[CH:21]([N+:28]([O-:30])=[O:29])[CH2:22][O:23]3)=[CH:18][C:17]=2[O:16]1
Reactant: O=[N+]([O-])C1=Cc2cc3c(cc2OC1)OCO3
Reactant: Brc1ccccc1C1OCCCO1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: BrCCBr
Product: O=[N+]([O-])C1COc2cc3c(cc2C1c1ccccc1C1OCCCO1)OCO3
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 61.4 %

Procedure:
Acetal (5a) (9.04 g, 37.22 mmol) was dissolved in 50 ml of dry THF under an inert atmosphere in a two necked flask equipped with a condenser. Magnesium (1.8 g, 74.44 mmol) and one drop of 1,2 dibromoethane were added. This mixture was stirred at 80° C. for 45 min, and cooled to room temperature. A 50 ml solution of 2.74 g of nitrochromene (3a) (12.41 mmol) in THF was cannulated into this flask. This mixture was stirred for 30 min, and water was added to quench the reaction. The mixture was extracted with CH2Cl2 (100 ml×3), the extracts washed with brine (100 ml), dried over MgSO4 filtered, and the solvent evaporated to a brown oil from which (6a) precipitated spontaneously. The precipitate was filtered, rinsed with 30 ml of EtOAc and dried to give 2.91 g (61.4% yield). The remaining liquor was purified by flash column chromatography to give an additional 550 mg (72% combined yield): mp 207° C.; 1H-NMR (CDCl3) δ 7.50 (m, 1, ArH); 7.29 (m, 2, ArH); 6.99 (m, 1, ArH); 6.47 (s, 1, ArH); 6.38 (s, 1, ArH); 5.90 (d, 2, ArOCH2); 5.70 (s, 2, OCH2O); 4.97 (s, 1, O2CHAr); 4.71 (dq, 1, Ar2CH, J=10 Hz); 4.23 (m, 2+1, CH2(CH2O)2, CHNO2); 3.98 (m, 2, CH2(CH2O)2); 2.22 (m, 1, CH2); 1.43 (d, 1, CH2); Low resolution CIMS: m/z (rel. intensity) 386 (MH+, 100). Anal. Calcd. for C20H19NO7: C, 62.33; H, 4.97; N, 3.63. Found: C, 62.18; H, 5.37; N, 3.38.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([C@@H:15]2[CH2:17][C@H:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([NH2:34])=[O:33])[CH2:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][C:32]([NH2:34])=[O:33])[CH2:27][CH2:26]3)[N:7]2[N:8]=1
Reactant: NC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccccc3)cc(Cl)n2n1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccccc3)cc(N3CCC(NC(N)=O)CC3)n2n1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
The title compound was prepared by combining (1R,2R)—N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8D, 0.08 g, 0.245 mmol) and the 1-(piperidin-4-yl)urea hydrochloride (0.088 g, 0.490 mmol) in NMP (0.816 ml) and heating the mixture at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by 40-60% preparatory HPLC (ACN/MeOH)/H2O+0.01% TFA). Lyophilization of the combined fractions gave 63 mg (59%) of the titled compound as a yellow solid. Melting point (160.1-165.7° C.). 1H NMR (DMSO-d6) δ: 10.95 (s, 1H), 7.24-7.35 (m, 3H), 7.14-7.24 (m, 3H), 6.08 (s, 3H), 4.24 (d, J=13.1 Hz, 2H), 3.66 (br. s., 2H), 3.17 (dd, J=23.7, 12.1 Hz, 2H), 2.39-2.47 (m, 1H), 2.26-2.38 (m, 4H), 1.90 (d, J=13.1 Hz, 2H), 1.34-1.59 (m, 4H); [α]D20=−202° (c=0.714, MeOH). ESI-MS: m/z 434.0 (M+H)+. Melting point (160.1-165.7° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23][N:24](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:23]([C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1)#[N:24]
Reactant: CCC(C)n1cc(-c2ccnc(Cl)c2)c(-c2ccc(Cl)s2)n1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC(C)n1cc(-c2ccnc(C#N)c2)c(-c2ccc(Cl)s2)n1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a solution of 2-chloro-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (0.28 mmol) in 1 mL of N,N-dimethylformamide was added zinc cyanide (0.14 mmol) and tetrakistriphenylphosphine palladium (O) (0.057 mmol). The resulting mixture was stirred in the microwave for 10 min at 120° C. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (column: Waters Sunfire C18, eluent:water/methanol/0.1% formic acid) to afford 56.7 mg of 2-cyano-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (55% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[CH2:4][CH2:3]1.CC1(C)C2C(=CC(/C=C/C3C=CC(C([O-])=O)=CC=3)=CC=2)N(C2C=CC(C)=CC=2)CC1.[Li+].[OH-]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:32])[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)N(c2ccc(C)cc2)CCC3(C)C)cc1
Agent: Cc1ccc(N2CCC(C)(C)c3ccc(/C=C/c4ccc(C(=O)[O-])cc4)cc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCC(C)(C)c3ccc(/C=C/c4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.033 g (0.08 mmol) of ethyl (E)-4-(2-(4,4-dimethyl-1,2,3,4-tetrahydro-N-(4-methylphenyl)quinolin-7-yl)ethenyl)benzoate (Compound 13) in 4.0 mL of tetrahydrofuran and 1.0 mL of methanol was added 1.0 mL (0.6 mmol) of 0.6M aqueous LiOH. The resulting solution was stirred at room temperature for 48 hours. The mixture was concentrated in vacuo, water was added, and the mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo, followed by recrystallization in acetonitrile to give the title compound as a solid. PNMR (300 MHz, DMSO) d 1.30 (6 H, s), 1.77 (2 H, t, J=6.0 Hz), 2.30 (3 H, s), 3.54 (2 H, t, J=6.0 Hz), 6.69 (1 H, s), 6.95-7.28 (8 H, m), 7.46 (2 H, d, J=8.4 Hz), 7.96 (2 H, d, J=8.4 Hz).
Reaction SMILES: [Ca:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3]>O>[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Ca+2:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Ca+2:1].[Ca+2:1]
Reactant: [Ca]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: [Ca+2]
Reaction time: 0.08 h

Procedure:
A solution of 218 g of disodium Na2HPO4.12H2O) in 1.2 liters of distilled water and a solution of 70 g of Ca(NO3)2.4H2O in 0.5 liters of distilled water were prepared. The calcium solution was quickly poured into the phosphate solution at room temperature with stirring. Precipitation was immediate and substantially complete. The precipitate was adjusted to pH 6.4 by the addition of sodium hydroxide solution in order to avoid the formation of acidic calcium phosphates. The precipitate was aged at room temperature for 5 minutes prior to filtration. The precipitate was then filtered through a Buchner filter (with a total surface about 0.1 m2), and was washed by about 3 liters of distilled water. A gel cake of low crystallinity calcium phosphate obtained on the filter paper.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[F:35][C:36]1[C:41]([F:42])=[C:40]([O:43][CH2:44][CH3:45])[CH:39]=[CH:38][C:37]=1[CH:46]1[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]1>C1COCC1>[F:35][C:36]1[C:41]([F:42])=[C:40]([O:43][CH2:44][CH3:45])[CH:39]=[CH:38][C:37]=1[CH:46]1[CH2:51][CH2:50][C:49](=[CH:9][CH2:8][CH:3]2[O:2][CH2:7][CH2:6][CH2:5][O:4]2)[CH2:48][CH2:47]1
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCC(=CCC3OCCCO3)CC2)c(F)c1F
Temperature: -30 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A mixture of 2-(1,3-dioxane-2-yl)-ethyltriphenyl phosphonium bromide (60.4 mmol) and 30 ml of THF was cooled down to −30° C. by use of a refrigerant under a nitrogen flow. To this mixture, t-BuOK (60.4 mmol) was added, and the mixture was stirred for one hour. A solution of the crude 4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexanone (50.3 mmol) dissolved in 100 ml of THF was added dropwise to this mixture while temperature was maintained at −30° C. or below. After completion of the addition, the reaction temperature was gradually elevated to room temperature, and the mixture was stirred for 2 hours. The reaction mixture was filtered with celite, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: a mixed solvent of ethyl acetate/toluene=3/7), the solvent was distilled off under reduced pressure, and the product was re-crystallized from heptane to form 2-(2-(4-(2,3-difluoro-4-ethoxyphenyl)cyclohexylidene)-ethyl)-1,3-dioxane (36.9 mmol).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH:5](=[N:3][CH2:2][CH2:1][N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCCN=Cc1ccccc1)c1ccccc1

Procedure:
A mixture of ethylenediamine (12.02 g; 0.2 mole) and benzaldehyde (42.44 g; 0.4 mole) in toluene (200 ml) was refluxed for 4 hours using a Dean-Stark trap. The toluene was then removed under vacuum. The residual oil crystallized on cooling. The resulting product was dried in a vacuum oven for 24 hours at room temperature and had a melting point of 52°-54° C.
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[C:10]2=[N:11][CH:12]=[CH:13][N:14]=[C:9]2[CH2:8][CH2:7][NH:6]1)[CH3:4].C(N(CC)C(C)C)(C)C.[C:24]([O:28][C:29]([NH:31][C@H:32]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[F:46])[CH2:33][C:34](O)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:24]([O:28][C:29]([NH:31][C@H:32]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[F:46])[CH2:33][C:34]([N:6]1[CH2:7][CH2:8][C:9]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[CH:5]1[CH2:3][CH3:4])=[O:35])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCC1NCCc2nccnc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1c2nccnc2CCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Ethyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine dihydrochloride (Intermediate 32, 26 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (DMF, 0.75 mL) containing N,N-diisopropylethylamine (0.046 mL, 34 mg, 0.26 mmol). (3R)-3-(tert-Butoxycarbonylamino)4 (2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 36 mg, 0.11 mmol), 1-hydroxybenzotriazole (16 mg, 0.12 mmol), and a portion of molecular sieve pellets (4 Å) were added, followed 10 min later by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol). After stirring for 16 h at room temperature, the mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was washed with saturated aqueous brine (10 mL) and the aqueous layers were extracted in succession with ethyl acetate (25 mL). The organic layers were dried over sodium sulfate, decanted, and evaporated. Purification by flash column chromatography (silica gel, 15-20% ethyl aceate/0.75-1.0% methanol/dichloromethane) gave the title compound as a mixture of diastereomers. Separation was accomplished by EPLC using a Chiralcel OJ column, eluting with 8% ethanol in hexanes. The first-eluting diastereomer was used in Step B to produce the more active final product. LC/MS: 501 (M+Na).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10](Cl)=[O:11]>C(Cl)Cl.O>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:11]
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: O
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a 0° C. solution of 2-amino-2-methylpropanol (10.1 g, 113.3 mmol) in CH2Cl2 (75 mL) under nitrogen was added dropwise a solution of 2,6-difluorobenzoyl chloride (10.0 g, 56.6 mmol) in CH2Cl2 (50 mL). The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was diluted with H2O, and the aqueous phase was extracted with CH2Cl2, dried (MgSO4) and concentrated. Purification via trituration with hexanes afforded 12.05 g (93%) of the amide, a white solid. 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 6 H), 3.66-3.75 (m, 2 H), 3.77-3.87 (m, 1 H), 5.94 (s, 1 H), 6.90-6.99 (m, 2 H), 7.31-7.41 (m, 1 H).