Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[C:9]1([CH3:24])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[NH2:16].O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:16]/[CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: O=Cc1ccccn1
Reactant: Cc1ccccc1C(N)c1ccccc1C
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C(/N=C/c1ccccn1)c1ccccc1C

Procedure:
In air, 2-pyridinecarboxaldehyde (36.0 mg, 32.0 μL, 0.336 mmol, 1.00 equiv) was added to a solution of di-o-tolylmethanamine (73.1 mg, 0.346 mmol, 1.03 equiv) in CH2Cl2 (5 mL). After heating at reflux for 30 min with azeotropic removal of water using a Dean-Stark trap, the reaction mixture was concentrated under reduced pressure and dried under high vacuum to give ligand (L-3), (E)-N-(Pyridin-2-ylmethylene)-1,1-dio-tolylmethanamine, as a yellow oil (0.102 g, 98% yield).
Reaction SMILES: [OH-].[K+].[OH:3][NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:11][CH2:12][CH2:13]Br.BrC(Br)(C)C>C(O)C>[CH2:8]([O:7][C:5]([N:4]1[CH2:13][CH2:12][CH2:11][O:3]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)NO
Reactant: BrCCCBr
Agent: CC(C)(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1CCCO1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
To a solution of KOH (6.4 g, 0.11 mol) and hydroxyurethane (12 g, 0.11 mol) in ethanol (50 mL) was added 1,3-dibromopropane (5.8 mL, 0.057 mol). The resulting suspension was heated at reflux for 1 hour. After the mixture was cooled to room temperature, an additional portion of KOH (3.2 g, 0.055 mol) and of dibromopropane (2.9 mL, 0.028 mol) was added. The mixture was then refluxed for 1 hour, cooled to room temperature, and solvent was evaporated. The residue was suspended in boiling ether three times and filtered. The combined filtrates were dried over sodium sulfate, filtered, and evaporated. A portion of 3 g of the crude product was purified by flush column chromatography (EtOAC/Hexane, gradient elution), yielding 1.18 g of N-(ethoxycarbonyl)isoxazolidine. 1 H NMR (CDCl3) δ 1.15(t, 3H), 2.15 (q, 2H), 3.55(t, 2H), 3.8 (t, 2H),4.1(q, 2H).
Reaction SMILES: [CH2:1]([O:5][PH:6]([CH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:19]=[O:20]>>[CH2:12]([O:11][CH2:10][CH2:9][CH2:8][P:6]([CH2:19][OH:20])(=[O:7])[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=O
Reactant: CCCCO[PH](=O)CCCOCc1ccccc1
Product: CCCCOP(=O)(CO)CCCOCc1ccccc1

Procedure:
The title compound was prepared from 3-benzyloxypropylphosphinic acid n-butyl ester and paraformaldehyde according to the method described in Procedure 31. Purification by chromatography, eluting with dichloromethane containing 5% methanol, gave an oil.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]([Cl:16])[C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[C:4]([Cl:17])[CH:3]=1.[Li]CC[CH2:21][CH3:22].[OH2:23]>C(OCC)C.C1COCC1>[Si:7]([O:6][C:5]1[C:14]([Cl:16])=[CH:15][C:2]([C:21](=[O:23])[CH3:22])=[CH:3][C:4]=1[Cl:17])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: [Li]CCCC
Reactant: O
Reactant: CC(C)(C)[Si](C)(C)Oc1c(Cl)cc(Br)cc1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of (4-bromo-2,6-dichlorophenoxy)(tert-butyl)dimethylsilane (from step 1, 15.2 g, 42.7 mmol) in diethyl ether (100 mL), n-BuLi (1.57 M in n-hexane, 27.2 mL, 42.7 mmol) was added at −78° C. and the mixture was stirred for 1 h. N,N′-dimethylacetamide (4.2 mL, 44 mmol) in THF (20 mL) was added at −78° C. and the mixture was stirred for 2 hours. The mixture was added water (100 mL) and extracted with diethyl ether (50 mL×3), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:10) to give title compound as a pale yellow oil (4.7 g, 34%).
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:11](=[CH:12][CH:13]=[C:5]2[O:4][CH2:3][C@@H:2]1[CH2:14][OH:15])[NH:10][CH:9]=[CH:8]3.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:15][CH2:14][C@H:2]2[O:1][C:6]3=[C:7]4[C:11](=[CH:12][CH:13]=[C:5]3[O:4][CH2:3]2)[NH:10][CH:9]=[CH:8]4)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: OC[C@H]1COc2ccc3[nH]ccc3c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc4[nH]ccc4c3O2)cc1

Procedure:
A solution of (S)-2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethanol (0.75 g; prepared by the method described above) in dichloromethane (50 ml) was stirred with cooling in an ice bath. 4-(Dimethylamino)pyridine (0.59 g) and 4-toluenesulphonyl chloride (0.84 g) were then added and the solution stirred at ambient temperature overnight. The mixture was diluted with dichloromethane (200 ml), washed sucessively with water (50 ml), saturated aqueous copper(II) sulphate solution (2×50 ml) and water (50 ml), then dried over sodium sulphate and the solvent evaporated to give (S)-2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl 4-toluenesulphonate (1.04 g) as a pale brown oil which solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.[OH-].[Na+].CO>C(O)CCC>[S:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1nc2ccccc2s1
Reactant: CCOC(=O)C(CCOC)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CO
Product: COCCC(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of ethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2-(2-methoxyethyl)-4oxobutanoate (75 mg, 0.21 mmol) in butanol (4 mL), 2-chloro-benzothiazole (43 mg, 0.25 mmol) was added and the reaction mixture was heated at 90° C. overnight. The solvent was removed by rotary evaporation, the residue was redissolved in DMF (1 mL), a solution of 1 N aqueous NaOH (0.63 mL, 0.63 mmol) was added, and the mixture was stirred at rt overnight. A solution of 1 N aqueous HC1 (0.3 mL, 0.3 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2-(2-methoxyethyl)-4-oxobutanoic acid as a white solid (30 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 2H), 7.95 (d, 2H), 7.70 (m, 5H), 7.60 (d, 1H), 7.30 (t, 1H), 7.15 (t, 2H), 3.35 (m, 2H), 3.25 (s, 3H), 3.20 (m, 2H), 2.90 (m, 1H), 1.95-1.75 (m, 2H); LC-MS ret. time 3.29 min (method 2), m/z 461.15 (MH+).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]([C:22]#[N:23])=[C:11]2[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)(=O)C.CO.[OH-].[Na+].O>O1CCCC1>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]([C:22]#[N:23])=[C:11]2[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1
Reactant: CC(=O)OCCOc1ccc2nc(CC(C)C)c(C#N)c(-c3ccc(C)cc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(OCCO)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of 2-{[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}ethyl acetate (4.0 g, 9.9 mmol) in tetrahydrofuran (20 ml)-methanol (20 ml) was added 2N aqueous sodium hydroxide solution (20 ml). The obtained mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give 6-(2-hydroxyethoxy)-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (3.2 g, yield 89%) as crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=2)[CH3:9])[CH:2]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=2)[CH3:9])[CH:2]=1
Reactant: COC(=O)c1ccc(C(C)Oc2cccnc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(Oc1cccnc1)c1ccc(C(=O)O)cn1
Temperature: 20 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
A mixture of methyl 6-(1-(pyridin-3-yloxy)ethyl)nicotinate (600 mg, 2.33 mmol), lithium hydroxide monohydrate (420 mg, 10 mmol), tetrahydrofuran (6 mL), methanol (2 mL) and water (2 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give 6-(1-(pyridin-3-yloxy)ethyl)nicotinic acid (550 mg, 97%).
Reaction SMILES: C[Mg]I.C(OC([C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:39])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[CH:22]=[CH:21]3)[CH:14]=[CH:13][N:12]=1)=O)(C)(C)C.C(Cl)Cl>C1COCC1.CO>[F:36][C:35]([F:38])([F:37])[C:31]1[CH:30]=[C:29]([NH:28][C:27]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][C:15]4[CH:14]=[CH:13][N:12]=[C:11]([C:15]([OH:17])([CH3:16])[CH3:14])[CH:16]=4)=[CH:26][CH:25]=3)[CH:21]=[CH:22]2)=[O:39])[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Agent: C[Mg]I
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Reaction time: 8 h

Procedure:
Methyl magnesium iodide (0.30 mL, 3.0 M) is added to a solution of 4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylic acid tert-butyl ester (0.150 g, 0.302 mmol) in THF (5 mL) at rt. After stirring overnight the reaction is diluted with MeOH (5 mL) and workup done with DCM and pH 7 buffer. Following concentration the residue is separated by FCC (80-100% EtOAc/heptane) to give the title compound. MS (ESI) m/z 456.1 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]2[O:9][CH:10]([C:13]([OH:15])=O)[CH2:11][O:12][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][NH2:29])=[CH:20][CH:19]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O1CCCC1>[C:1]([C:5]1[CH:17]=[CH:16][C:8]2[O:9][CH:10]([C:13]([NH:29][CH2:28][C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=[CH:19][CH:20]=3)=[O:15])[CH2:11][O:12][C:7]=2[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccnc2ccccc12
Reactant: CC(C)(C)c1ccc2c(c1)OCC(C(=O)O)O2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc2c(c1)OCC(C(=O)NCc1ccnc3ccccc13)O2
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of 6-tert-Butyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (27 mg, 0.11 mmol), quinolin-4-yl-methanamine (15 mg, 0.09 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (43 mg, 0.11 mmol) in DMF (0.4 mL) was added N,N-diisopropylethylamine (82 μL, 0.47 mmol). Tetrahydrofuran (0.8 mL) was added to dilute the solution. The reaction was left to stir overnight then concentrated and attempted purification by HPLC using 20-80% acetonitrile/water. Product isolated was less than 95% pure. It was purified again using 30-60% acetonitrile/water to obtain the product (23 mg, 64%) as a solid. m/z=376.8 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ 8.89-8.81 (m, 1H), 8.76-8.72 (m, 1H), 8.16-8.13 (m, 1H), 8.04-8.02 (m, 1H), 7.80-7.75 (m, 1H), 7.66-7.61 (m, 1H), 7.11 (t, 1H, J=4.63 Hz), 6.93-6.89 (m, 2H), 4.99-4.95 (m, 1H), 4.93-4.73 (m, 2H), 4.41-4.28 (m, 2H), 1.24 (d, 9H, J=1.94 Hz).
Reaction SMILES: [C:1]([S:20]/[CH:21]=[CH:22]\[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[I:30].[CH2:31](OCC)C>C(Cl)Cl>[I-:30].[C:1]([S:20]/[CH:21]=[CH:22]\[C:23]1[CH:24]=[N+:25]([CH3:31])[CH:26]=[CH:27][CH:28]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CI
Reactant: CCOCC
Reactant: C(=C\c1cccnc1)\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C[n+]1cccc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-[(Z)-2-(tritylthio)vinyl]pyridine (5 g) and methyl iodide (8.3 ml) in dry methylene chloride (100 ml) was stirred at ambient temperature for 24 hours. The reaction mixture was poured into diethyl ether under stirring. The resultant precipitate was collected by filtration, washed with diethyl ether and air-dried at ambient temperature to give 3-[(Z)-2-(tritylthio)vinyl]-1-methylpyridinium iodide (6.64 g) as yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][N:4]1[C:12]([C:14]1[N:15]=[C:16]([CH3:25])[S:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13].[O:26]1[C:30]2=[CH:31][CH:32]=[CH:33][C:34]([C:35](O)=[O:36])=[C:29]2[CH:28]=[CH:27]1>>[CH3:25][C:16]1[S:17][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:14]([C:12]([N:4]2[CH2:5][C@@H:6]3[C@H:11]([CH2:10][CH2:9][CH2:8][CH2:7]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]3[O:26][CH:27]=[CH:28][C:29]=23)=[O:36])=[O:13])[N:15]=1
Reactant: Cc1nc(C(=O)N2CC3CCCCC3C2CN)c(-c2ccccc2)s1
Reactant: O=C(O)c1cccc2occc12
Product: Cc1nc(C(=O)N2C[C@H]3CCCC[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)c(-c2ccccc2)s1

Procedure:
The pair of stereo isomers Examples 70 and 71 were isolated by preparative HPLC from the coupling reaction according general procedure A (1-(aminomethyl)-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)(2-methyl-5-phenylthiazol-4-yl)methanone and benzofuran-4-carboxylic acid. The assignment of stereochemistry is not verified. MS (ESI) 500 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:37])[N:25]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:26]=[C:27]([Cl:29])[CH:28]=2)=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].O.[OH-].[Li+].C(OCC)(=O)C>C1COCC1.O>[CH2:30]([N:25]1[CH:26]=[C:27]([Cl:29])[CH:28]=[C:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C@@H:4]([C:3]([OH:38])=[O:2])[NH:5][C:6]([C:8]3[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:15])=[O:7])=[CH:22][CH:21]=2)[C:24]1=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1)C(=O)O
Yield: 0.7 %

Procedure:
A solution of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1-benzyl-5-chloro-2-oxo-pyridinyl)-L-phenylalanine methyl ester (72 mg, 0. 13 mmol) in THF (3 mL) was treated with a solution of lithium hydroxide monohydrate (22 mg, 0.52 mmol) in water (1.0 mL). Additional THF was added to effect a clear solution and the reaction mixture was stirred 1.5 hr at which time, TLC (ethyl acetate) indicated starting material was consumed. A few drops of acetic were added and the entire reaction mixture was applied to a 4×30 cm, C-18 reversed phase HPLC column and eluted with a linear gradient of acetonitrile in water of 5 to 95% over 35 min. The product containing fraction was lyophillyzed to give 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-N-[(2-chloro-6-methylphenyl)carbonyl] -L-phenylalanine (50 mg, 71%) as a white solid. LR-Electrospray: m/z negative ion 533 (M−H (2 Cl)); positive ion 557(M+Na), 552 (M+NH4), 535 (M+H (2 Cl)). HRMS: Obs. Mass 535.1190. Calcd. Mass 535.1191 (M+H).
Reaction SMILES: C[O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:40](Cl)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]>ClCCl>[CH3:42][C:41]([CH3:44])([CH3:43])[C:40]([N:8]1[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([CH3:23])[NH:4][C:3]1=[O:2])=[O:45]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(=O)N(C(=O)C(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (0.96 g., 3.0 mmole), dry triethylamine (1.25 ml., 9.0 mmole), and dimethylaminopyridine (36 mg., 0.3 mmole) in dichloromethane (12 ml.) under argon is treated with pivaloyl chloride (0.44 ml., 3.6 mmole). After stirring for 45 minutes at room temperature, the reaction mixture is evaporated. The residue is taken up in tetrahydrofuran/methanol (10 ml. each) and treated with 2N hydrochloric acid (6.0 ml., pH 1). After stirring at room temperature for 3.0 hours, the reaction is quenched with saturated sodium bicarbonate, partially evaporated and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride and evaporated. Flash chromatography and crystallization from dichloromethane/isopropyl ether gives the title compound as white crystals (420 mg. , m. p. 155°-156°. TLC(silica gel; ethyl acetate:hexane, 1:1)Rf =0.67.
Reaction SMILES: C1(CO[C:9](=O)[N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29](=[O:31])[CH3:30])[C@@H:24]([CH3:32])[CH2:23][C@H:22]4[NH:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=3)=[CH:15][CH:14]=2)C)C=CC=CC=1.[ClH:42]>C(O)C.CO.[Pd]>[ClH:42].[C:29]([N:25]1[C:26]2[C:21](=[CH:20][C:19]([C:16]3[CH:15]=[CH:14][C:13]([CH2:12][NH:10][CH3:9])=[CH:18][CH:17]=3)=[CH:28][CH:27]=2)[C@H:22]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=2)[CH2:23][C@@H:24]1[CH3:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N1c2ccc(-c3ccc(CN(C)C(=O)OCc4ccccc4)cc3)cc2[C@H](Nc2ccc(F)cn2)C[C@@H]1C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CNCc1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(F)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48 %

Procedure:
A mixture of phenylmethyl[(4-{(2S,4R)-1-acetyl-4-[(5-fluoro-2-pyridinyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}phenyl)methyl]methylcarbamate (for a preparation see intermediate 79) (55 mg, 0.100 mmol) and palladium (10% w/w on charcoal, 50% wet, 6.35 mg, 0.060 mmol) in ethanol (9 mL) was stirred under hydrogen (1 bar) at room temperature for 17 h then filtered through celite. The insoluble material was rinsed with ethanol (20 mL) and the combined filtrate and washings were concentrated in vacuo. Purification of the residue with MDAP (modifier: ammonium bicarbonate) gave a white solid which was dissolved in MeOH (0.4 mL), then treated with HCl (1.25M in MeOH, 38.3 μL, 0.0478 mmol). The resulting mixture was concentrated in vacuo to give (2S,4R)-1-acetyl-N-(5-fluoro-2-pyridinyl)-2-methyl-6-{4-[(methylamino)methyl]phenyl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (23 mg, 48%) as a pale yellow solid.
Reaction SMILES: [OH2:1].[C:2](#[N:5])[CH:3]=[CH2:4]>CC(C)=O>[CH:4]1[C:2]([NH2:5])=[CH:3][CH:4]=[C:2]([N+:5]([O-:1])=[O:1])[CH:3]=1
Reactant: C=CC#N
Reactant: O
Solvent: CC(C)=O
Product: Nc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 120 parts of acrylonitrile and 1000 parts of acetone is introduced into the solution of the diazo derivative obtained from 276 parts of p-nitraniline. Then 40 parts of cupric chloride cyrstallised with 2 molecules of water are added and the mixture is kept vigorously stirred. The evolution of nitrogen is exothermal and the temperature must be maintained at 30°-32° C. by means of a cooling bath. After the diazonium chloride has disappeared (six hours), the yellow flakes which melt at 108° C. are filtered off. After recrystallising from methanol, 330 parts of 2-chloro-4'-nitro-3-phenyl-propionitrile are obtained which melts at 112° C. The product obtained is then dehydrohalogenated by means of 200 parts of crystalline sodium acetate in a mixture of 340 parts of water and 800 parts of ethyl alcohol. The mixture is heated under reflux for 12 hours and 225 parts of 4-nitro-cinnamonitrile which melts at 202° C. are isolated in the cold.
Reaction SMILES: [O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].Br[CH2:28][CH2:29][S:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:28][CH2:29][S:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: BrCCSc1nccs1
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Product: COC(=O)[C@H]1CN(CCSc2nccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12

Procedure:
Methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-ylthio)ethyl]piperidine-3-carboxylate was prepared, by analogy with Example 4, from methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate and 2-bromo-1-(1,3-thiazol-2-ylthio)ethane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:10]2([CH2:13][CH:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][C:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][C:27]1([NH:31][C:20]([CH:17]2[CH2:16][CH2:15][N:14]([CH:12]3[CH2:13][C:10]4([CH2:23][CH2:24][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]4)[CH2:11]3)[CH2:19][CH2:18]2)=[O:22])[CH2:30][CH2:29][CH2:28]1
Reactant: CC1(N)CCC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(N3CCC(C(=O)O)CC3)C2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(NC(=O)C2CCN(C3CC4(CCN(C(=O)OC(C)(C)C)C4)C3)CC2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
1-[6-(tert-Butoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid was dissolved in DMF (5 mL) and (1-methylcyclobutyl)amine hydrochloride (0.37 g, 3.03 mmol), HATU (0.844 g, 2.22 mmol) and DIPEA (1.305 g, 10.1 mmol) were added. The reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 A, 50 mL per min, gradient 0% to 10% MeOH in DCM]) to give tert-butyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.627 g, 76.7%) as a white foam.