Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3](=[O:30])[C:4]2[CH:5]=[CH:6][N:7]3[C:20](=[O:21])[N:19](COCC[Si](C)(C)C)[N:18]=[C:8]3[C:9]=2[O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:1][C:2]1[C:3](=[O:30])[C:4]2[CH:5]=[CH:6][N:7]3[C:20](=[O:21])[NH:19][N:18]=[C:8]3[C:9]=2[O:10][C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)CCOCn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(I)c(-c2ccccc2)oc2c1ccn1c(=O)[nH]nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.1 %

Procedure:
To a stirred ice-cooled solution of 7-iodo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalene-3,6-dione (60 mg, 0.112 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was allowed to warm to RT. After 16 hours, the solvents were removed in vacuo, the residue was dissolved in THF (2 mL) and benzyltrimethylammonium hydroxide (40% in MeOH, 0.05 mL) was added. The reaction mixture was stirred at RT for 1 hour. EtOAc was added and the mixture was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (50.4 mg) as a buff solid. LCMS (Method B): RT=3.84 min, [M+H]+=406.
Reaction SMILES: [CH3:1][O:2][Na].[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19](Cl)[CH:18]=[CH:17]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CO>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([O:2][CH3:1])[CH:18]=[CH:17]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Clc1ccc2cccc(OCc3ccccc3)c2n1
Reactant: CO[Na]
Solvent: CO
Solvent: O
Product: COc1ccc2cccc(OCc3ccccc3)c2n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
To a solution of MeONa (400 mg, 7.43 mmol) in MeOH (20 mL) was added 8-(benzyloxy)-2-chloroquinoline (2.0 g, 7.43 mmol). The mixture was stirred at 70° C. for 16 h. To the mixture was added H2O (20 mL) and the product extracted with toluene (30 mL×3). The combined organic layers were dried with Na2SO4 and evaporated to give the desired compound (1.5 g, yield 79%). LCMS (m/z): 266.1 [M+H]+
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12])=[O:3].F[C:14]1C=CC(OC)=C(C(O)(C)C)C=1>>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([C:2]([OH:3])([CH3:14])[CH3:1])[CH:9]=1
Reactant: COc1ccc(F)cc1C(C)(C)O
Reactant: COc1ccc(Cl)cc1C(C)=O
Product: COc1ccc(Cl)cc1C(C)(C)O

Procedure:
2-(5-chloro-2-methoxyphenyl)propan-2-ol (m.p. 56° C.) was prepared from 5-chloro-2-methoxyacetophenone following the method described in Example 3 for the preparation of 2-(5-fluoro-2-methoxyphenyl)propan-2-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.C([Li])(C)(C)C.[C:17](=[O:19])=[O:18]>>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[C:17]([OH:19])=[O:18]
Reactant: Fc1cc2[nH]ncc2cc1Br
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Product: O=C(O)c1cc2cn[nH]c2cc1F

Procedure:
This compound was prepared in a manner similar to that shown in Scheme 3, using 5-bromo-6-fluoro-1H-indazole (88d), which was treated with t-butyl lithium and carbon dioxide to yield 6-fluoro-1H-indazole-5-carboxylic acid. This compound in turn was treated with thiosemicarbazide and polyphosphoric acid to form 5-(6-fluoro-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine. MS (API-ES) m/z (%): 236 (100%, M++1).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)[CH3:3].Cl[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:27]=1>O1CCOCC1>[CH2:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:27]=2)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:10]=1)[CH3:3]
Reactant: Fc1ccc(COCCl)cc1Oc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OCC)cc1
Agent: [Na]
Solvent: C1COCCO1
Product: CCOC(=O)C(COCc1ccc(F)c(Oc2ccccc2)c1)(C(=O)OCC)c1ccc(OCC)cc1
Temperature: 0 °C
Yield: 52.2 %

Procedure:
Sodium (2.18 g, 35 mmol) was added to diethyl 4-ethoxyphenylmalonate (26.6 g, 95 mmol) dissolved in dioxane (100 ml) and refluxed until the sodium had dissolved. Chloromethyl(4-fluoro-3-phenoxybenzyl)ether (25.4 g, 95 mmol) was added, dropwise, at 40°-50° C. and then heated under reflux for 3 hours. The mixture was added to ice-water, extracted three times with ether, the extracts washed with water, dried over magnesium sulphate and evaporated. After chromatography on silica-gel, using toluene as the eluent, there was obtained 25.3 g of diethyl 2-(4-ethoxyphenyl)-2-(4-fluoro-3-phenoxybenzyloxymethyl)malonate (52% of theory). This was then reduced in a similar manner to Example 1 using lithium aluminium hydride to give crude 2-(4-ethoxyphenyl)-2-(4-fluoro-3-phenoxybenzyloxymethyl)propane-1,3-diol.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].CCCCCC.Br[CH2:20][CH2:21][OH:22]>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:20][CH2:21][OH:22])[N:3]=1
Reactant: OCCBr
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1c(Br)nn(CCO)c1Br
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A solution of 3,5-dibromo-4-nitropyrazole (2) (11.0 g, 41 mmol) in DMF (52 ml) was added dropwise over 20 min to a stirred solution of NaH (1.76 g, 46 mmol; 60% dispersion in oil, prewashed with hexane under an inert atmosphere) in DMF (88 ml). After stirring for 10 minutes, a solution of 2-bromoethanol (6.4 g, 49 mmol) in DMF (14 ml) was added dropwise over 10 minutes. The reaction mixture was heated to 80° C. for 2 hours and then the DMF was evaporated off under reduced pressure. A mixture of DCM/water (100 ml, 1/1) is added to the residue and the organic phase is washed with water (50 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude brown solid obtained was subsequently purified by column chromatography (5%/95% EtOAc/hexane). The yellow solid product (3.4 g) was recrystallized from a mixture of toluene/hexane (20 ml, 55%/45%) to give the 2-(3,5-dibromo-4-nitropyrazol-1-yl)ethanol (3) in the form of a white solid (2.8 g, 22%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][CH:9]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:10]=[O:11].[OH-].[Na+]>CCOCC>[CH3:8][CH:9]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:10][OH:11]
Reactant: CC(C)CCCC(C)CCCC(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)CCCC(C)CCCC(C)CO
Reaction time: 1 h

Procedure:
To a solution of 70 ml. of 70% by weight of bis (2-methoxyethoxy) sodium aluminum hydride in toluene (0.25 mol) in 500 ml. of anhydrous diethyl ether was added, dropwise over 1.0 hour, 69.2 g. (0.326 mol.) of (±)-2,6,10-trimethylundecanal. The solution was stirred 1.0 hour, poured onto ice and 10N aqueous NaOH, and worked up with ether and dried as described in Example 2. Distillation of the crude product gave (±)-2,6,10-trimethylundecan-1-ol as a colorless oil; b.p. 96°-98° C./0.20 mmHg.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3ccc(F)cc3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.46 ml, 4.45 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 147 (1.4 g, 4.45 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (1.0 g of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 7:3).
Reaction SMILES: [OH-].[Na+].Cl.[CH:4]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[C:11]([F:20])[C:10]([O:21][CH:22]([CH3:24])[CH3:23])=[C:9]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH:37]=[CH:36][C:35]([C:38]([O:40]C)=[O:39])=[C:34]([CH3:42])[C:33]4=[O:43])[CH2:28][CH2:27]3)[CH:8]=2)[CH2:6][CH2:5]1.O>CO>[CH:4]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)=[C:11]([F:20])[C:10]([O:21][CH:22]([CH3:24])[CH3:23])=[C:9]([CH2:25][N:26]3[CH2:27][CH2:28][CH:29]([N:32]4[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[C:34]([CH3:42])[C:33]4=[O:43])[CH2:30][CH2:31]3)[CH:8]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC2)c(=O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
2M aqueous sodium hydroxide solution (690 mL) was added to a solution of methyl 1-(1-((6-cyclopropyl-2,4′-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate hydrochloride (270 g) in methanol (1.35 L) at room temperature. The mixture was stirred at 50 C for 2 hours and cooled to room temperature. Water (2.70 L) was added to the reaction mixture. The mixture was concentrated in vacuo to remove methanol and neutralized with 2M hydrochloric acid (460 mL) at room temperature. Crystalline seeds were added to the mixture. The mixture was stirred at room temperature for 17 hours. The precipitate was collected by filtration, washed with water (7.00 L) and dried in vacuo at 65 C for 24 hours to give the title compound (245.3 g).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:7]([O:6][C:4](=[O:5])[C@@H:3]1[CH2:9][CH2:10][CH2:11][N:1]([CH2:13][CH2:14][OH:15])[CH2:2]1)[CH3:8]
Reactant: CCOC(=O)C1CCCNC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCO)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The (R)-enantiomer of ethyl nipecotate (100 g, 0.64 mole) (Akkerman, A.M. et al., Gazz.Chim.Ital., 102 (1972) 189) was mixed in dry acetone (300 ml) with 2-bromoethanol (85 g, 0.68 mole), dried, powdered potassium carbonate (188 g, 1.28 mole) and potassium iodide (21.6 g, 0.13 mole). The reaction mixture was stirred at room temperature for 18 h and at reflux for 24 h. Filtration of the reaction mixture and evaporation of the resultant filtrate gave (R)-1-(2-hydroxyethyl)nipecotic acid ethyl ester as an oil, which was purified by distillation in vacuo (110°-° C., 0.1 mmHg), yield (72.2 g, 56%). TLC: rf 0.20 (SiO2 ; dichloromethane/methanol 19/1).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1ccccc1CC(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Solvent: CC#N
Product: COc1ccccc1CC(=O)N1CC[C@@](CCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-methoxyphenyl)acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]([OH:27])([CH3:26])[CH3:25])[N:18]=[C:17]2[CH2:28][CH2:29][CH3:30])=[CH:11][CH:10]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:27][C:24]([C:19]1[N:18]=[C:17]([CH2:28][CH2:29][CH3:30])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:33][N:32]=[N:31][N:2]=3)=[CH:14][CH:13]=2)[C:20]=1[C:21]([OH:23])=[O:22])([CH3:25])[CH3:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 45 %

Procedure:
Into the same device as used in Example 34 were placed 43.5 g (0.10 mole) of ethyl ester of 1-(2'-cyanobiphenyl-4-yl)methyl -4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid, 8.5 g (0.13 mole) of sodium azide, 20.8 g (0.15 mole) of triethylamine hydrochloride and 206 ml of toluene. The mixture was reacted and treated in the same manner as in Example 34, giving 20.3 g (0.045 mole) of 4-(1-hydroxy-1-methylethyl) -2-propyl-1-{4-[2-(tetrazole -5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid (yield 45.0% based on ethyl ester of 1-(2'-cyanobiphenyl -4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([CH2:35][O:36]C(=O)C)=[O:34]>>[OH:36][CH2:35][C:33]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:34]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: O=C(NC1CCN(C(=O)CO)CC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A159) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Li]CCCC.[NH2:12][C:13]1[C:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:17][C:16]([Cl:27])=[CH:15][C:14]=1[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C1COCC1>[NH2:12][C:13]1[C:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:21])[CH3:22])=[CH:17][C:16]([Cl:27])=[CH:15][C:14]=1[C:28]([OH:33])([C:2]#[C:3][CH:4]1[CH2:6][CH2:5]1)[C:29]([F:32])([F:31])[F:30]
Reactant: C#CCCCCl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)C(F)(F)F)c1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(O)(C#CC2CC2)C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70.4 %

Procedure:
To a stirred, cooled (0° C.) solution of 31.8 mL (300 mmol) of 5-chloro-1-pentyne in 250 mL of THF was added 252 mL (630 mmol) of 2.5 M n-BuLi in hexanes over 20 min. Over the course of the addition the internal temperature had warmed to ambient temperature, and the mixture was stirred at this temperature for 40 min. The reaction was cooled to −20° C. and treated with a solution of 32.7 g (97.4 mmol) of 2′-amino-5′-chloro-3′-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone in 50 mL of THF over 10 min. The dark solution was stirred an additional 30 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 800 mL of 0° C. 1 N citric acid with rapid stirring. The mixture was extracted twice with ether, and the combined organic extracts were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 28.8 g (70%) of (+/−)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an off-white solid, mp 125-126° C. 1H NMR (300 MHz, CDCl3) δ7.22(d, 1H, J=2.2 Hz); 6.76(d, 1H, J=2.2 Hz) ; 4.86(br. s, 1H); 4.39(br. s, 2H); 1.32-1.43(m, 1H); 1.02(s, 9H); 0.79-0.92(m, 4H); 0.27(s, 3H); 0.26(s, 3H). High resolution mass spec: calculated for C19H26NO2ClF3Si(M+H)+: 420.1373, found: 420.1363.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10]1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(CC3CCCCC3)C2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1cnc(N[C@@H]2CCN(CC3CCCCC3)C2)c(Cl)c1
Yield: 99.9 %

Procedure:
A solution of ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (330 mg) and 1N NaOH solution (1.5 ml) in MeOH (30 ml) was stirred at 80-85° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture was AcOEt and H2O. The aquous solution was adjusted to PH 5.4 with 5% HCl solution and resultant solution was evaporated in vacuo and the residue was dissolved in a MeOH and THF. The solvent was evaporated in vacuo and dried to give (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (306 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(Br)c1
Yield: 91 %

Procedure:
A stirred solution of (3-bromophenyl)acetic acid (10.0 g, 0.0465 mol) and concentrated sulfuric acid (4.5 mL) in MeOH (230 mL) was heated at 40° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was mixed with water (50 mL) and DCM (100 mL). The layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% EtOAc/hexanes) to give the title compound (19.8 g, 91% yield) as a colorless oil.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:19])[NH:6][C:7]1[N:8]([CH2:16][CH2:17][OH:18])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:30]1[N:34]2[CH:35]=[C:36]([O:39][C@H:40]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[C@@H:43]([NH2:50])[CH2:42][CH2:41]3)[CH:37]=[CH:38][C:33]2=[N:32][N:31]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:50][C@@H:43]2[C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[C@H:40]([O:39][C:36]3[CH:37]=[CH:38][C:33]4[N:34]([C:30]([C:24]5[C:23]([Cl:22])=[CH:28][CH:27]=[CH:26][C:25]=5[Cl:29])=[N:31][N:32]=4)[CH:35]=3)[CH2:41][CH2:42]2)=[O:19])[N:8]([CH2:16][CH2:17][OH:18])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4c(Cl)cccc4Cl)n3c2)c2ccccc21
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(-c5c(Cl)cccc5Cl)n4c3)c3ccccc32)n(CCO)n1
Temperature: 60 °C
Reaction time: 42 h
Yield: 14.3 %

Procedure:
A mixture of Intermediate 26a (100 mg, 0.279 mmol), Intermediate 26d (108 mg, 0.254 mmol), and DIPEA (73 μL, 0.419 mmol) in dioxane (2.5 mL) was stirred at 60° C. for 42 h and then left standing at RT for 72 h. The volatiles were concentrated in vacuo and the resultant residue was purified by FCC, using 0-10% MeOH in DCM followed by MDAP (Method 7) to afford the title compound (23 mg, 14%) as a white solid. LCMS (Method 5): Rt 4.19 min, m/z 634 [MH+]. 1H NMR (400 MHz, DMSO): 1.21 (9H, s), 1.79-2.16 (4H, m), 3.62-3.70 (2H, m), 3.94 (2H, t, J=6.0 Hz), 4.78-4.88 (1H, m), 4.99 (1H, br s), 5.55 (1H, t, J=4.2 Hz), 6.05 (1H, s), 7.07 (1H, d, J=8.6 Hz), 7.23-7.30 (1H, m), 7.31-7.38 (4H, m), 7.70-7.74 (1H, m), 7.74-7.80 (2H, m), 7.91 (1H, d, J=9.9 Hz), 7.98 (1H, d, J=2.1 Hz), 8.19 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:23][Si:24]([CH:27](O)[CH3:28])([CH3:26])[CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([O:16][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(O)[Si](C)(C)C
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(-c2ccccc2C(=O)OCC[Si](C)(C)C)cc1
Reaction time: 3 h

Procedure:
The starting material can be obtained, for example, as follows: 14.2 g of 4-methyl-2'-carboxybiphenyl (EP 253,310) are dissolved in 60 ml of acetonitrile and 10.7 ml of pyridine and 11.4 ml of trimethylsilylethanol are added. The mixture is treated at 0° with 15.1 g of dicyclohexylcarbodiimide and stirred at this temperature for 3 hours. After this, the reaction mixture is evaporated in a high vacuum, the residue is treated with ether, and dicyclohexylurea is filtered off. After flash chromatography (ethyl acetate/hexane 95:5), 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl is obtained as a slightly yellowish oil. (TLC: ethyl acetate/hexane 95:5) Rf : 0.42. 312 mg of 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl, 178 mg of N-bromosuccinimide, 5 mg of azoisobutyronitrile and 15 ml of carbon tetrachloride are heated to reflux for one hour. After cooling, the mixture is evaporated. Flash chromatography (ethyl acetate/hexane 95:5) yields 4-bromomethyl-2'-(trimethylsilylethoxycarbonyl)biphenyl as a slightly yellowish oil. 1H-NMR (CFCl3): 0 ppm (s, 9H), 0.7 ppm (t, 2H), 4.5 ppm (s, 2H), 7.1-8 ppm aromatics.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11](=[CH2:22])[C:12]([O:14]CC3C=CC=CC=3)=[O:13])[C:5]2=[N:4][N:3]=1>[Pd].CO>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([CH3:22])[C:12]([OH:14])=[O:13])[C:5]2=[N:4][N:3]=1
Reactant: C=C(C(=O)OCc1ccccc1)c1cccn2c(C)nnc12
Agent: [Pd]
Solvent: CO
Product: Cc1nnc2c(C(C)C(=O)O)cccn12
Reaction time: 6 h
Yield: 77.6 %

Procedure:
To 0.040 mg (0.038 mmol) of 10% palladium on carbon was added a solution of (0.080 g, 0.27 mmol) of benzyl 2-(3-methyl[1,2,4]triazolo[4,3-a]pyridin-8-yl)acrylate prepared in Step C above in 4 mL of methanol. The resulting suspension was stirred under an atmosphere of hydrogen (1 atmosphere) for 6 h. The residue was filtered through a pad of Celite® and the pad was washed cold methanol. The combined filtrates were evaporated under reduced pressure to give yield the title compound (0.043 g, 77%). LC-MS: iniz (ES) 206 (MH)+.