Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11](/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[C:19]([O:21]CC)=[O:20])=[CH:10][C:9]=1[CH3:24].[OH-].[Na+]>CO.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:9]([CH3:24])=[CH:10][C:11](/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:12][C:13]=1[CH3:14]
Reactant: CCOC(=O)/C=C/C=C/c1cc(C)c(OCOCCOC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOCOc1c(C)cc(/C=C/C=C/C(=O)O)cc1C
Yield: 85.4 %

Procedure:
To a stirred solution of ethyl 5-[4-{(2-methoxyethoxy)methoxy}-3,5-dimethylphenyl]-(2E,4E)-2,4-pentadienoate (5.28 g) in methanol (55 ml) was added a solution of sodium hydroxide (6.32 g) in water (18 ml) below 20° C. After being stirred for an hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (200 ml) and adjusted to pH 4 with 10% hydrochloride solution. The resulting precipitate was collected by filtration and washed with water to give yellowish powder of 5-[4-{(2-methoxyethoxy)methoxy}-3,5-dimethylphenyl]-(2E,4E)-2,4-pentadienoic acid (4.13 g).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[CH3:8][Si:9]([CH3:15])([CH3:14])[Si:10]([CH3:13])([CH3:12])Cl>[Zn].CN1CCCC1=O>[CH3:12][Si:10]([CH3:13])([CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])[Si:9]([CH3:15])([CH3:14])[CH3:8]
Reactant: C[Si](C)(C)[Si](C)(C)Cl
Reactant: O=C1OCCC1Br
Agent: [Zn]
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)[Si](C)(C)C1CCOC1=O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
200 ml of N-methylpyrrolidone and 34.3 g of zinc dust are placed in a 1,000 ml three-neck flask fitted with internal thermometer, cold-drawn precision glass stirrer and dropping funnel. A mixture of 82.5 g of 2-bromo-γ-butyrolactone and 83.4 g of pentamethylchlorodisilane and 100 ml of N-methylpyrrolidone is added dropwise while stirring so that the internal temperature adjusts to 60° C. during the exothermic reaction. Stirring is continued for a further 6 h at this temperature and the reaction mixture is then poured onto 500 g of flaked ice. Once the ice has melted, the organic phase which separates is separated off and the aqueous phase is extracted with 200 ml of cyclohexane. The combined organic phases are distilled off using a rotary evaporator after drying over magnesium sulfate and the residue is distilled in vacuo.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH:22]([NH:25][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:24])[CH3:23]
Reactant: CCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: CC(C)N
Product: CCCc1noc(C)c1COc1ccc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29.9 %

Procedure:
A mixture of 6-(5-methyl-3-propyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (290 mg, 1.0 mmol), isopropylamine (71 mg, 1.2 mmol) and TBD (42 mg, 0.30 mmol) was stirred for 15 h at ambient temperature under argon. The reaction mixture was concentrated onto silica then purified by chromatography (silica, 0 to 60% ethyl acetate in heptane) to give the title compound (95 mg, 30%) as a white solid after trituration with diisopropyl ether. MS: m/e=318.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH2:24])[C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:24][S:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:40])=[O:39])[C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](N)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COc1ccc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-[(2S)-2-Amino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester of Step G (40 mg, 0.072 mmol) is stirred in pyridine (0.5 mL) at 0° C. under N2. Benzenesulfonyl chloride (20 mg, 0.11 mmol) is added and the reaction is stirred overnight at RT. The mixture is then diluted with CH2Cl2 (20 mL), washed with 2N HCl (2×20 mL) and then with saturated NaHCO3 (2×20 mL). The organics are dried over MgSO4, filtered, concentrated and purified by flash column chromatography to provide 5-[(2S)-2-benzenesulfonylamino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:17]([N:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:20])=[O:18]>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:20][N:19]([C:17](=[O:18])[C:16]1[CH:15]=[C:14]([CH3:13])[CH:27]=[C:26]([CH3:28])[CH:25]=1)[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:8]
Reactant: Cc1cc(C)cc(C(=O)N(N)C(C)(C)C)c1
Reactant: COc1cccc(C(=O)O)c1C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A solution of 3-methoxy-2-methylbenzoic acid (1.5 g, 0.01 tool) in thionyl chloride (10 mL) was refluxed for 45 minutes and then stripped under reduced pressure. The residue was dissolved in methylene chloride (50 mL) and added dropwise with cooling at 0° C. to a solution of N-(3,5-dimethylbenzoyl)-N-tertbutylhydrazine (4.4 g. 0.02 mol) in methylene chloride (50 mL). Following the addition, the solution was stirred overnight at room temperature and filtered. The filter-cake was washed extensively with water and ether, and then dried in vacuo to give 2.1 g (64.1% yield) of N-(3-methoxy-2-methylbenzoyl)-N'(3,5-dimethylbenzoyl)-N'-tert-butylhydrazine, melting at 204-204.5° C. 1H-NMR δppm 1.50 (s, 9H, tert-Bu), 1.63 (s, 3H, Ar-CH3), 2.25 (s, 6H, di-CH3) 3.75 (s, 6.26 (d, 1H, Ar), 6.93-7.20 (m, 5H, Ar).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:4][N:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>C(O)C>[CH3:13][O:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:4][N:3]=1
Reactant: CCOC(=O)c1onc(O)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)c1onc(OC)c1C
Temperature: 40 °C

Procedure:
A mixture of ethyl 3-hydroxy-4-methylisoxazole-5-carboxylate (2.0 g, 11.7 mmol) and K2CO3 (4.0 g, 29 mmol) in ethanol (50 mL) was heated at 40° C. for a total of 26 h. Methyl iodide (0.8 mL, 13 mmol) was added after 1 h and an additional 3 times during the next 25 h. The solution was filtered and reduced in vacuo (according to 1H NMR, a 1:1 mixture of the title compound and ethyl 3-methoxy-4-methylisoxazole-5-carboxylate was obtained). Flash chromatography (silica gel, eluent: dichloromethane/diethyl ether=9:1 then 1:1) gave ethyl 3-Methoxy-4-methylisoxazole-5-carboxylate as a yellow oil (0.40, 18%) and title compound (0.45 g, 21%). A small sample of the latter was recrystallized (EtOAc/heptane) to give colorless crystals: mp 64-65° C. Crude title compound was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[N:10]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[C:26]([N:45]1[C:49]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:56]2[CH:63]=[CH:62][C:59]([CH2:60]Br)=[CH:58][CH:57]=2)=[N:48][N:47]=[N:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:60][C:59]2[CH:58]=[CH:57][C:56]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=3[C:49]3[N:45]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:46]=[N:47][N:48]=3)=[CH:63][CH:62]=2)[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11]([OH:14])([CH3:12])[CH3:13])[N:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(COC(C)=O)nc1C(C)(C)O
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1c(C(C)(C)O)nc(COC(C)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 61 %

Procedure:
Following a procedure similar to that described in Example 82(a), but using 730 mg of ethyl 2-acetoxymethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate [prepared as described in Preparation 48(iii)], 320 mg of potassium t-butoxide and 2.11 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and then purifying the product by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate, 1.23 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C1NCCn2c1cc1cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Temperature: 0 °C
Yield: 47.7 %

Procedure:
To the solution of 0.5 g (2.5 mmol) 8-hydroxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1, intermediate a)) in 10 mL tetrahydrofuran, 0.6 g (3.0 mmol) 1-(tert-butoxycarbonyl)-4-hydroxypiperidine and 0.78 g (3.0 mmol) triphenylphosphine were added. The solution was cooled to 0° C., 0.68 g (3.0 mmol) di-tert-butyl azodicarboxylate were added and the cooling bath was removed. After 18 hours the reaction mixture was evaporated and the residue was flash-chromatographed on silica gel with dichloromethane: methanol: ammonia (9:1:0.1 v/v) as eluant to give 0.46 g (49%) of the desired compound as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:19][CH3:20])[CH:9]=2)[N:4]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)CCC.CN(C=O)C>CCOC(C)=O.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>[CH2:19]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][CH3:18])[C:11]=1[C:8]1[CH:9]=[C:10]2[C:2]([C:35]3[S:36][CH:37]=[CH:38][N:39]=3)=[CH:3][N:4]([C:21]3[CH:22]=[CH:23][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:25][CH:26]=3)[C:5]2=[CH:6][N:7]=1)[CH3:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CCc1cccc(CC)c1-c1cc2c(Br)cn(-c3ccc(C(C)C)cc3)c2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1cc2c(-c3nccs3)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (50 mg, 0.11 mmol), 2-tributylstannanyl-thiazole (83 mg, 0.22 mmol), Pd(PPh3)4 (20 mg, 0.017 mmol), and DMF (3 mL) is stirred under nitrogen at 100° C. for 18 h. The mixture is diluted with EtOAc (15 mL) and washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue gives 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-3-thiazol-2-yl-1H-pyrrolo[2,3-c]pyridine as colorless oil: 1H NMR (CDCl3) 9.03 (s, 1H), 8.15 (s, 1H), 7.84 (d, J=1 Hz, 1H), 7.56 (d, J=12 Hz, 2H), 7.46 (d, J=12 Hz, 2H), 7.32 (t, J=7 Hz, 1H), 7.31-7.26 (m, 3H), 7.20 (s, 1H), 3.05 (m, 1H), 2.39 (m, 4H), 1.35 (d, J=8 Hz, 6H), 1.09 (t, J=8 Hz, 6H); LCMS m/z 452.23 (2.93 min).
Reaction SMILES: CC1CCCCC1=[O:8].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18]O)=[O:17])[CH:11]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[OH:8][CH:14]([CH3:13])[CH2:15][CH2:10][CH2:11][CH2:12][C:16]([OH:18])=[O:17]
Reactant: CC1CCCCC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(O)CCCCC(=O)O
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A solution of 2-methylcyclohexanone (11.1 g, 0.099 mol) in chloroform (15 ml) was added during 20 minutes, under nitrogen, to a stirred suspension of m-chloroperbenzoic acid (24.6 g, 0.143 mol) in chloroform (250 ml). After 3 hours, 40 minutes, the mixture was poured into aqueous sodium bicarbonate and extracted with methylene chloride. The extract was washed with brine, dried (MgSO4) and concentrated. The residue was distilled from a small amount of K2CO3 to give 9.58 g, bp 78°-79° C. (2.5-3 mm Hg) of 6-hydroxyheptanoic acid, ε-lactone.
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:19])[CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH2:14]([O:19][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CC(C)CCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (230 mg, 10 mmol) in isopentanol (20 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].O.[CH3:21][C:22]([CH3:25])([O-:24])[CH3:23].[K+]>CN(C)C=O>[C:22]([O:24][CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4])([CH3:25])([CH3:23])[CH3:21]
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 10.6 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), water (0.010 mL, 0.56 mmol), and potassium tert-butoxide (0.10 g, 0.90 mmol) in dimethylformamide (5 mL) provided 2-tert-butoxy-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.015 g) after reverse-phase HPLC purification.MS (ES) m/z 260.1 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=O>>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][NH:1][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: O=Cc1ccccn1
Reactant: NCCCO
Product: OCCCNCc1ccccn1

Procedure:
prepared by reaction of 3-amino-propan-1-ol with pyridine-2-carbaldehyde
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[NH2:12].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[F:10][C:8]([F:11])([F:9])[C:6]1[CH:7]=[C:2]2[CH:1]=[N:13][NH:12][C:3]2=[CH:4][N:5]=1
Reactant: Cc1cc(C(F)(F)F)ncc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cc2cn[nH]c2cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-methyl-6-(trifluoromethyl)pyridin-3-amine [944317-54-8] (1.00 g, 5.68 mmol) in acetic acid (75 mL) was treated with a solution of sodium nitrite (392 mg, 5.68 mmol) in water (1 mL). The reaction mixture was stirred at RT for 15 min and then was allowed to stand at ambient temperature for 48 h. Acetic acid was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHCO3. The organic solution was washed with water and brine, then dried (Phase separator) and concentrated under vacuum. MS (LC-MS): 188 [M+H]+, tR (HPLC conditions k): 2.49 min.
Reaction SMILES: [K+:1].[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11](=[CH2:15])[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[K+:1].[C:2]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10][C@@H:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C

Procedure:
100 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid potassium salt (2-a, R1=Boc, R2=H, R3=CO2K) (prepared according to procedure in Example 42) is added to ethanol (1 ml). 10% Palladium on carbon (10 mg, 50% water wet, Degussa type E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with ethanol (2×1 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-a, R1=Boc, R2=H, R3=CO2K) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-b, R1=Boc, R2=H, R3=CO2K). 1H NMR (CDCl3): 1.06-1.12, 1.31-1.36, 1.80-0.193, 2.25-2.49, 2.62-2.92, 3.74-4.08, 4.81 and 5.27, 6.20 and 6.54, 7.24-7.57.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:15][CH:16]([CH2:21][OH:22])[C:17]([O:19][CH3:20])=[O:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]([C:6]([NH:15][CH:16]([CH2:21][OH:22])[C:17]([O:19][CH3:20])=[O:18])=[O:8])=[CH:4][N:3]=1
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)O
Reactant: COC(=O)C(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CO)NC(=O)c1cnc(Cl)cc1NC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-chloro-4-(isopropylamino)nicotinic acid (9) (1.3 g, 6.06 mmol) in DMF (25 mL), methyl 2-amino-3-hydroxypropanoate (12.11 mmol) and DIPEA (18.17 mmol) were added followed by the addition of HATU (30.3 mmol) to the reaction mixture and stirred at room temperature for 2 h. DMF was removed under reduced pressure. The residue obtained was diluted with EtOAC and washed with water and 10% NaHCO3 solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by flash chromatography using silica gel and EtOAC: pet ether as eluent to afford the title compound, methyl 2-(6-chloro-4-(isopropylamino)nicotinamido)-3-hydroxypropanoate. LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.312 min; LCMS (ES-API), m/z 316.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[N:10]([C@@H:16]([CH2:36][CH2:37][CH:38]([F:41])[CH2:39][NH2:40])[CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH3:48][O:49][C:50]([NH:52][C@H:53]([C:67](ON1C(=O)CCC1=O)=[O:68])[CH:54]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51]>C1COCC1.O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9](=[O:42])[N:10]([C@@H:16]([CH2:36][CH2:37][CH:38]([F:41])[CH2:39][NH:40][C:67](=[O:68])[C@H:53]([CH:54]([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[NH:52][C:50]([O:49][CH3:48])=[O:51])[CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:33])[CH3:34])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCN(C(=O)OCc1ccccc1)[C@@H](CCC(F)CN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)ON1C(=O)CCC1=O)C(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CCC(C)C)C(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a stirred solution of the material from Step 10 (86 mg, 0.145 mmol) in THF (1 mL) and water (333 μL) at 0° C. was added NaHCO3 (49 mg, 0.58 mmol) and followed by portionwise addition of 2,5-dioxopyrrolidin-1-yl N-(methoxycarbonyl)-β-phenyl-L-phenylalaninate (63 mg, 0.16 mmol). The reaction mixture was stirred at room temperature overnight, poured into brine, and extracted with EtOAc (2×). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 110 mg of the title compound. 1H NMR (DMSO-d6): δ 8.24-8.12 (m, 1H), 7.67-7.53 (m, 4H), 7.51-7.37 (m, 6H), 7.37-7.20 (m, 11H), 7.19-7.07 (m, 2H), 7.03-6.91 (m, 1H), 5.15-4.90 (m, 3H), 4.29-4.19 (m, 1H), 3.96-3.76 (m, 1H), 3.74-3.47 (m, 2H), 3.06 (s, 3H), 3.16-2.97 (m, 4H), 2.96-2.76 (m, 1H), 1.55-1.28 (m, 5H), 1.27-1.01 (m, 2H), 0.97 (s, 9H), 0.85 (d, J=4.2 Hz, 3H), 0.77 (d, J=4.20 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc(C(=O)OC)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(C(C)Br)n1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of methyl 6-ethylpyridine-2-carboxylate (587 mg) in carbon tetrachloride (28.4 mL) were added N-bromosuccinimide (696 mg) and benzoyl peroxide (75%, 11.5 mg). The mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool to ambient temperature. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (702 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[CH3:15][C:12]1[S:13][CH:14]=[C:10]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:3][CH:4]=2)[N:11]=1
Reactant: C1CCNCC1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2ccc(N3CCCCC3)nc2)cs1
Temperature: 90 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 0.25mL (2.5 mmol, 3 eq) piperidine and 2 mL DMF were combined. The reaction mixture was heated at 90° C. for 16 h, quenched with pH 10 PBS, extracted with DCM. Silica gel chromatography (gradient 10% to 50% EtOAc/Hexanes) gave 5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2-piperidin-1-ylpyridine (L-001106455). The mono HCl salt was made by dissolving the free base into diethyl ether, adding 1 eq of HCl, and isolated by filtration. LC-MS calculated for C16H17N3S 283, observed m/e 284.3 (M+H)+. 1H-NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.92-7.93 (m, 2H), 7.30 (d, 1H), 3.73 (m, 4H), 2.68 (s, 3H), 1.61-1.66 (m, 6H).