Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([Cl:13])[N:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([Cl:13])[N+:3]=1[O-:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1c(Cl)cc(C)nc1Cl
Solvent: ClCCl
Product: CCCCc1c(Cl)cc(C)[n+]([O-])c1Cl

Procedure:
66 g of 2-methyl-4,6-dichloro-5-n-butyl-pyridine are dissolved in 600 ml of methylene chloride and a solution of 66 g of 85% strength m-chloroperbenzoic acid in 600 ml of methylene chloride is added dropwise over the course of 21/2 hours whilst stirring. Thereafter, the mixture is stirred for a further 48 hours at room temperature. The reaction solution is extracted by shaking with aqueous ferrous sulphate solution and with 2 N sodium carbonate solution. The methylene chloride solution is dried and evaporated. 2-Methyl-4,6-dichloro-5-n-butyl-pyridine-N-oxide is thus obtained as the residue. This is taken up in 300 ml of toluene and 82 ml of acetic anhydride are added over the course of 15 minutes whilst stirring. Thereafter the mixture is boiled under reflux for 15 hours. The reaction solution is evaporated. The residue is taken up in ether and extracted by shaking with 2 N sodium carbonate solution. The ether solution is dried and evaporated. After fractionation of the residue, 2-acetoxymethyl- 4,6-dichloro-5-n-butyl-pyridine is obtained.
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.[C:33]([Cu])#[N:34]>CC(N(C)C)=O.C(OCC)(=O)C>[C:33]([C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3)#[N:34]
Reactant: N#C[Cu]
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](COc1cc2c(cc1C#N)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
In a 25 mL sealed tube, (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (150 mg, 0.297 mmol) (as prepared in Ex. 3, Part A) was taken up in DMA (4 mL). To this mixture was added CuCN (53.3 mg, 0.595 mmol) and the mixture heated at 150° C. for 24 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL) and filtered through diatomaceous earth (Celite®). The ethyl acetate solution was washed with brine (10 mL) and water (10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the crude product as gummy solid which was carried forward without further purification. LC/MS (ESI) m/e 451.2 [(M+H)+, calcd for C25H31N4O4, 451.5]; LC/MS retention time (method B): tR=2.02 min.
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH:3]=O.[CH3:12][C:13]([CH3:27])([CH3:26])[CH2:14][C@H:15]([NH2:25])[C:16]12[O:23][CH2:22][C:19]([CH3:24])([CH2:20][O:21]1)[CH2:18][O:17]2>>[F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH:3]=[N:25][C@H:15]([C:16]12[O:17][CH2:18][C:19]([CH3:24])([CH2:20][O:21]1)[CH2:22][O:23]2)[CH2:14][C:13]([CH3:27])([CH3:12])[CH3:26]
Reactant: O=CC(F)(F)c1ccccn1
Reactant: CC(C)(C)C[C@H](N)C12OCC(C)(CO1)CO2
Product: CC(C)(C)C[C@H](N=CC(F)(F)c1ccccn1)C12OCC(C)(CO1)CO2

Procedure:
DIBAL-H (2 ml) was added to a solution of 2,2-difluoro-2-pyridin-2-ylacetic acid ethyl ester (400 mg, 2 mmol) in dry ether (2.5 ml) at −78° C. After 4 h, methanol (0.5 ml) and water (2 ml) were added. The reaction mixture was warmed to room temperature and the emulsion formed was filtered through celite and washed with ether. The organic layer was separated, washed with brine and dried over MgSO4. The solvent was evaporated to get a thick liquid. To the crude liquid was added DCM (1 ml) and hexane (3 ml) and left overnight in cold. The precipitated solid was filtered and washed with hexane to give 2,2-difluoro-2-pyridin-2-ylacetaldehyde (150 mg) as a white solid. 2,2-Difluoro-2-pyridin-2-ylacetaldehyde was reacted with 3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butylamine as described in Example 1, Step 8 above to give (2,2-difluoro-2-pyridin-2-ylethylidene)-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amine (600 mg) as a thick liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=[C:5]([O:17][CH3:18])[N:4]=1.CN(CCN(C)C)C.C([Li])CCC.Cl[C:33]([O:35][CH3:36])=[O:34]>CCOCC>[C:33]([C:7]1[CH:6]=[C:5]([O:17][CH3:18])[N:4]=[C:3]([O:2][CH3:1])[C:8]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])([O:35][CH3:36])=[O:34]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(OC)n1
Reactant: COC(=O)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC(=O)c1cc(OC)nc(OC)c1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
The product of Example 27 (1 g, 3.93 mmol) was dissolved in Et2O (35 mL) and TMEDA (1.7 mL, 1.18 mmol) and cooled to -78° C. n-Butyllithium (4.75 mL, 11.87 mmol) was added dropwise and the reaction was allowed to stir for 15 minutes at -78° C. before warming to -10° C. for 2.5 hours. The solution was cooled back to -78° C. and methyl chloroformate (0.6 mL, 7.8 mmol) dissolved in Et2O (4.5 mL) was added dropwise. The reaction was held at -78° C. for 10 minutes and then warmed to -10° C. and allowed to stir for 1.5 hours before quenching with NH4Cl (sat). The reaction mixture was extracted 3× with EtOAc. The organics were combined, washed with brine, dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography using hexane/ethyl acetate as eluant (gradient 9/1 to 4/1) to provide 0.423 g (34%) of tert-butyl N-(4-carbomethoxy-2,6-dimethoxy-3-pyridyl)carbamate as a white solid. Electrospray Mass Spec: 312.8 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8]>C1(C)C=CC=CC=1.C1COCC1>[CH:7]([C@H:6]1[C:10](=[O:11])[O:12][C:1](=[O:2])[NH:5]1)([CH3:9])[CH3:8]
Reactant: O=C(Cl)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@@H]1NC(=O)OC1=O
Temperature: 55 °C
Yield: 47.32 %

Procedure:
30.4 ml (57.47 mmol, 1.08 eq.) of a 20% solution of phosgene in toluene were added slowly at r.t. to a stirred solution of 6.26 g (53.44 mmol) L-valine (81a) in 63 ml dry THF. After the complete addition the mixture was heated at 55° C. for 4 h. Then a stream of nitrogen was bubbled through the solution and passed after that through a 1M aq. NaOH-solution for 20 min. before the solvent was evaporated. Recrystallization of the obtained residue from PE/Ether (2:1) yielded 3.62 g (25.29 mmol, 47.32%) (S)-4-Isopropyl-oxazolidine-2,5-dione (86) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(#N)C>[Br:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: COC(OC)OC
Reactant: Nc1ccc(Br)cc1C(=O)NC1CCC(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: O=C1CCC(n2cnc3ccc(Br)cc3c2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide (0.51 g, 1.5 mmol) and trimethyl orthoformate (2 mL) and p-toluene sulfonic acid (150 mg) in acetonitrile (10 mL) was heated to reflux for 12 hours. To the mixture, was added water (70 mL), and stirred at room temperature for 2 hours. The suspension was filtered and washed with ethyl acetate (10 mL). The solid in NMP (3 mL) was heated at 80° C. To the solution, was added water (1.5 mL), and the mixture was allowed to cool to room temperature. The suspension was filtered and washed with NMP (1 mL) and ethyl acetate (10 mL) to give 3-(6-bromo-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (350 mg, 68% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.18 min (99.9%); mp: 312-314° C.; 1H NMR (DMSO-d6) δ 2.14-2.21 (m, 1H, C W), 2.60-2.74 (m, 2H, 2CHH), 2.83-2.93 (m, 1H, CHH), 5.51 (brs, 1H, NCH), 7.68 (d, J=9 Hz, 1H, Ar), 8.03 (dd, J=2, 9 Hz, 1H, Ar), 8.24 (d, J=2 Hz, 1H, Ar), 8.42 (s, 1H, CH), 11.19 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.45, 30.93, 55.49, 119.83, 122.96, 128.23, 129.65, 137.61, 146.52, 147.94, 158.66, 169.75, 172.46: LCMS: MH=336, 338; Anal Calcd for C13H11N3O3Br+0.3H2O: C, 45.72; H, 3.13; N, 12.30; Br, 23.39. Found: C, 45.46; H, 2.75; N, 12.15; Br, 22.81.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CCCC(CCCC(F)(F)C(F)(F)F)C(O)=O)[C:7]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)([CH2:12][CH2:13][CH3:14])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:44][C:45]([F:71])([C:61]([F:70])([F:69])[C:62]([F:68])([F:67])[C:63]([F:66])([F:65])[F:64])[CH2:46][CH2:47][CH:48]([CH2:54][CH2:55][CH2:56]CCC=C)[C:49]([O:51]CC)=[O:50]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:56][CH2:55][CH2:54][CH:48]([CH2:47][CH2:46][C:45]([F:44])([F:71])[C:61]([F:70])([F:69])[C:62]([F:67])([F:68])[C:63]([F:64])([F:65])[F:66])[C:49]([OH:51])=[O:50])[C:7]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)([CH2:12][CH2:13][CH3:14])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 29 and ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared separately, the same procedure as shown in Example 13 was repeated to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[OH-].[Na+].[Br:11][CH2:12][C:13](Cl)=[O:14]>ClCCl>[Br:11][CH2:12][C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)=[O:14]
Reactant: Cc1cccc(N)c1
Reactant: O=C(Cl)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cccc(NC(=O)CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of m-toluidine (15.5 mL, 140 mmol) in a 2N aqueous solution of sodium hydroxide (75 mL) was added dropwise a solution of bromoacetyl chloride (11.6 mL, 140 mmol) in dichloromethane (50 mL) and the reaction mixture was stirred at room temperature for about 30 min. The layers were separated and the organic layer was washed with 1N aqueous hydrochloric acid, dried (MgSO4), filtered and concentrated under vacuum. The residue was triturated twice from dichloromethane/hexane (1:4) to provide 2-bromo-N-m-tolyl-acetamide. MS (DCI-NH3): m/z 245, 247 (M+NH3)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([NH2:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[N+:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:17][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([O-:10])=[O:9]
Reactant: CCCCCCN
Reactant: O=[N+]([O-])c1cccc(Br)c1
Product: CCCCCCNc1cccc([N+](=O)[O-])c1
Yield: 78.3 %

Procedure:
Using the general procedure, 3-bromonitrobenzene (202 mg, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (6:1) as eluent afforded the desired product as a light yellow solid (174 mg, 78% yield). Rf=0.5 (hexane/ethyl acetate=5:1).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13](C2C=CC=CC=2)[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[C:29](C1N2CCNCC2=C(C(N[C@@H](C(C)(C)C)C(NC)=O)=O)N=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([C:13]1[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]2=[C:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:1])([CH3:28])[CH3:27])[C:4]([NH:6][CH3:7])=[O:5])=[O:10])[N:12]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CC2)C(C)(C)C
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(C(=O)c2ccccc2)n2c1CNCC2)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1nc(C(=O)c2ccccc2)n2c1CN(C)CC2)C(C)(C)C

Procedure:
Compound 289 was synthesized in the same manner as described above for Compound 48 in Example 5 except that 25C was used in place of Compound 2. 1H-NMR (400 MHz, CD3OD) δ: 1.04 (s, 9H), 2.55 (s, 3H), 2.75 (d, 3H), 2.93 (t, 2H), 4.03 (d, 2H), 4.35 (d, 1H), 4.56 (t, 2H), 7.53 (t, 2H), 7.64 (m 1H), 7.86 (d, 1H), 8.19 (m, 1H), 8.31 (d, 2H); LCMS (+ESI) m/z 412.1 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([S:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][S:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: ClCCCCCSCc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCSCc2ccccc2)CC1
Yield: 28.7 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.2 g) and 5-benzylthiopentyl chloride (1.4 g) were reacted and treated in the same manner as in Example 168 to give 0.57 g of 4-amino-N-((1-(5-benzylthiopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30][NH2:31]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30][NH:31][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2S(C)(=O)=O)n(C)c(=O)c1O
Product: Cn1c(-c2ccc(F)cc2S(C)(=O)=O)nc(C(=O)NCc2ccc(Cl)c(Cl)c2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (74.07 mg, 0.20 mmol) and 3,4-dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (69 mg, 92% yield). 1HNMR (500 MHz, CDCl3) δ: 12.00 (1H, s), 7.87 (1H, dd, J=7.63, 2.45 Hz), 7.60 (1H, t, J=7.60 Hz), 7.50–7.42 (2H, m), 7.39 (1H, d, J=7.93 Hz), 7.32 (1H, s), 7.11 (1H, d, J=7.32 Hz), 4.55 (1H, dd, J=15.26, 6.41 Hz), 4.49 (1H, dd, J=15.26, 6.10 Hz), 3.26 (3H, s), 3.06 (3H, s). HRMS (ESI) calcd for C20H17Cl2FN3O5S (M+H): 500.0250; found: 500.0259.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([C:14]([O:16][CH3:17])=[O:15])#[C:9][C:10]([O:12][CH3:13])=[O:11]>CO>[NH:1](/[C:9](=[CH:8]\[C:14]([O:16][CH3:17])=[O:15])/[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1
Solvent: CO
Product: COC(=O)/C=C(\Nc1ccccc1)C(=O)OC

Procedure:
Purified aniline (15.0 g, 0.16 mole) was reacted with dimethyl acetylenedicarboxylate (19.8 ml, 0.15 mole) in 400 ml methanol according to the procedure of Heindel, et al., J. Het. Chem. 1966, 3, 222. The reaction was refluxed for 18 hours, then worked up by evaporating the solvent, dissolving the residue in ether, and washing consecutively with 0.5 N HCl, H2O, and sat. NaCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica gel in 80/20 hexane/EtOAc which yielded 29.14 g of the Michael Adduct, dimethyl anilinofumarate as a light yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=O)(C)(C)C.C(OC([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27]O)=O)(C)(C)C.N.[ClH:30]>>[ClH:30].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:25]1[CH:26]=[N:22][C:27]([Cl:30])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: Cl
Agent: N
Product: Clc1ccc(OC[C@H]2CCCN2)cn1

Procedure:
Following the procedures described in Example 45 steps a-c, substituting (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol for the (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol of step 45a thereof, the title compound was prepared. mp 157-159° C. MS (DCI/NH3) m/e: 213/215 (M+H)+ and 230/232 (M+NH4)+. 1H NMR (D2O, 300 MHz) δ: 8.10 (d, J=3.0 Hz, 1H), 7.53-7.43 (m, 2H), 4.45 (dd, J=10.7, 7.7 Hz, 1H), 4.15-4.08 (m, 1H), 3.41 (t, J=7.2 Hz, 2H), 2.34-1.88 (m, 4H). Anal. Calc. for C10H14Cl2N2O·0.3 HCl: C, 46.18; H, 5.54; N, 10.77; Found C, 46.35; H, 5.51; N, 10.66.
Reaction SMILES: [C:1](C(C#N)=C(C#N)C#N)#[N:2].ClCCO[CH:15]([O:23][CH2:24][CH2:25][Cl:26])[C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[N:20][CH:21]=1>C(#N)C>[Cl:26][CH2:25][CH2:24][O:23][CH:15]([C:16]1[CH:21]=[N:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:1]#[N:2]
Reactant: ClCCOC(OCCCl)c1ccc(Cl)nc1
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: CC#N
Product: N#CC(OCCCl)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 471.2 %

Procedure:
Trimethylsilyl cyamide (1.88 mL) and tetracyanoethylene (240 mg) were added to a solution of 5-[bis-(2-chloroethoxy)methyl]-2-chloropyridine (2.67 g) in acetonitrile (50 mL), and the reaction solution was heated under reflux for five hours. The reaction solution was left to cool to room temperature, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the resulting residue. The organic layer washed with brine and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=8:1) to obtain 2.04 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][CH3:12])(=[O:10])[O:6]C(C)C>Cl>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][CH3:12])(=[O:6])[OH:10]
Reactant: CCP(=O)(CCCN)OC(C)C
Agent: Cl
Product: CCP(=O)(O)CCCN
Reaction time: 14 h

Procedure:
A mixture of 7.73 g of isopropyl 3-aminopropyl(ethyl)-phosphinate and 40 ml of 20% hydrochloric acid is refluxed with stirring for 14 hours. The clear solution is evaporated to dryness and the residue is recrystallized from methanol/propylenoxide to give 3-aminopropyl(ethyl)phosphinic acid as a white solid, m.p. 233°-239°; 1H-NMR (D2O): 0.4-1.8 (m, 9H, PCH2CH2 and PCH2CH3); 2.7 (t, 2H, NCH2); 4.55 (s, 3H, OH, NH2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH:12]2[CH2:15][O:14][CH2:13]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=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.[NH2:49][C@@H:50]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:51]([NH:53][CH3:54])=[O:52]>CN(C=O)C>[CH3:56][C:55]([CH3:58])([CH3:57])[C@H:50]([NH:49][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH:12]2[CH2:15][O:14][CH2:13]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:51](=[O:52])[NH:53][CH3:54]
Reactant: O=C(O)c1cc(OC2COC2)c(Cl)cn1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
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: CNC(=O)[C@@H](NC(=O)c1cc(OC2COC2)c(Cl)cn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Chloro-4-(oxetan-3-yloxy)-pyridine-2-carboxylic acid (Example 23a, 35 mg, 152 μmol) in DMF (1 mL) was added HATU (58 mg, 152 μmol) and DIEA (66.6 μL, 381 μmol). The reaction mixture was then stirred at room temperature for 30 min, followed by addition of (S)-2-amino-N,3,3-trimethylbutanamide (CAN 89226-12-0, 22 mg, 152 μmol). The reaction mixture was stirred for 3 h. The crude reaction mixture was directly purified by preparative HPLC to deliver the desired compound (17.5 mg, 32%) as a yellow oil. MS (ESI, m/z): 356.5 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(N(CC)CC)C.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>ClCCl>[NH:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCNCC1)c1cccs1
Reaction time: 0.08 h

Procedure:
Commercially available tert-butyl 4-aminopiperidine-1-carboxylate (0.50 g, 1.0 eq) was taken up in dichloromethane and treated with triethylamine (0.42 mL, 1.2 eq). After stirring for 5 minutes, thiophene-2-carbonyl chloride (0.29 ml, 1.1 eq) was slowly added. The reaction stiffed for 15 hours at room temperature. To work up, dichloromethane (5 mL) was added. The organics were washed with water (3×-5 mL) then dried over Na2SO4 and concentrated for 0.80 g tan oil (obs M+Na 323, calc M+Na 323). This product was dissolved in dioxane (5 mL) and treated with 4 N HCl in dioxane (1.88 ml). After stiffing for 15 hours at room temperature, the reaction was concentrated to oily residue (0.63 g, 100% over 2 steps, calc M+H 211, obs M+H 211).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][S:4][N:3]=1.[CH3:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C=O)C>[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([C:2]2[C:6]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[N:5][S:4][N:3]=2)[CH2:16][CH2:15]1
Reactant: CC1CCNCC1
Reactant: Clc1nsnc1-c1cccnc1
Solvent: CN(C)C=O
Product: CC1CCN(c2nsnc2-c2cccnc2)CC1

Procedure:
A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (10.80 g, 4 mmol) and 4-methylpiperidine (1.96 g, 20 mmol) in DMF (10 ml) was heated at 100° C. for 3 h. After evaporation water was added to the residue and extracted with ether. The combined and dried organic phases were evaporated and the residue purified by column chromatography (SiO2, eluent: ethyl acetate/methylene chloride (1:2)). Yield: 0.8 g (77%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH3:18].O>CN(C)C=O>[CH2:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1])[CH3:18]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-chloronicotinic acid (5 g, 31.7 mmol, Aldrich) in dimethylformamide (50 mL) were added potassium carbonate (6.579 g, 47.6 mmol) and ethyl iodide (3.8 mL, 47.7 mmol), respectively. The reaction mixture was stirred at room temperature for 3 d. Water (˜50 mL) was added and the product was extracted with ethyl ether (2×75 mL). The combined organic phases were washed with brine (1×50 mL), dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated under reduced pressure to give 2-chloronicotinic acid ethyl ester as yellow oil. It was then dissolved in ethanol (50 mL) and sodium ethoxide (17.8 mL, 47.6 mmol, 21% in ethanol, Aldrich) was added dropwise. Precipitation was seen as sodium ethoxide was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated and the residue partitioned between methylene chloride (150 mL) and water (50 mL). The aqueous layer was extracted with methylene chloride (1×50 mL). The combined organic layers were washed with brine (1×20 mL) and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (120 g of silica gel, 10-30% ethyl acetate in hexane) to give 2-ethoxynicotinic acid ethyl ester as an orange oil (4.04 g, 65% yield for 2 steps).