Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:22]2[C:21](=[O:27])[CH2:20][C@@:19]2([CH3:28])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:18])[CH2:16][OH:17])[CH2:6]1)(=[O:3])[CH3:2].[CH3:29]I>[Ag]=O>[C:1]([O:4][C@@H:5]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:22]2[C:21](=[O:27])[CH2:20][C@@:19]2([CH3:28])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:18])[CH2:16][O:17][CH3:29])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CO)[C@@]4(C)CC(=O)[C@@H]32)C1
Reactant: CI
Agent: O=[Ag]
Product: COCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 8 h

Procedure:
Freshly prepared silver oxide (690 mg.) was added to a solution of 3α-acetoxy-21-hydroxy-5β-pregnane-11,20-dione (68.3 mg.) in methyl iodide (1.5 ml.) and the resulting mixture was refluxed for 1 hour, allowed to stand overnight and then refluxed for a further 3 hours. The reaction was partitioned between water and chloroform and the chloroform layer was washed with water, dried (Na2SO4) and evaporated to give 3α-acetoxy-21-methoxy-5β-pregnane-11,20-dione (69 mg.) as a foam. This was dissolved in methanol (1.25 ml.) and refluxed with 10% aqueous potassium bicarbonate solution (0.6 ml.) for 2.5 hours. The reaction mixture was allowed to cool and was partitioned between water and ether. The ether layer was washed with water, dried (Na2SO4) and evaporated. The product was purified by preparative t.l.c. (ethyl acetate:chloroform; 1:1) to give the title compound as a foam, [α]D + 80°, (c 2.36).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]#[N:17])[CH2:12][CH2:11]1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH3:30])[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:18]([O:22][C:23](=[O:24])[NH:25][C@H:26]([C:27](=[O:28])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]#[N:17])[CH2:14][CH2:15]1)[CH3:30])([CH3:19])([CH3:20])[CH3:21]
Reactant: N#C[C@H]1CC[C@H](Nc2cc(F)ccc2N)CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@H]1CC[C@H](C#N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of trans-4-(2-amino-5-fluorophenylamino)cyclohexanecarbonitrile (195 mg, 0.83 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (174 mg, 0.92 mmol), HOAt (125 mg, 0.92 mmol), 4-methylmorpholine (0.20 mL, 1.83 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (192 mg, 1.0 mmol) in THF (3 mL) was stirred at RT for 18 h under a nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and water. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a white foam (199 mg, 60%). LCMS (Method B): RT 3.37 [M+H]+ 405.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[CH:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](OC2C=CC=CC=2)=[N:22][C:23]#[N:24])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:23]([NH:22][C:21](=[N:6][C:5]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[O:20][C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)#[N:24]
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N=C(NC#N)Oc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.3 %

Procedure:
To a solution of 3-methyloxy-5-trifluoromethylaniline (11 mmol, 2.10 g) in dichloromethane (25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g) and triethylamine (11 mmol, 1.53 ml) were added. The reaction mixture was stirred under nitrogen for 16 h at room temperature. After concentration the residue was stirred with water, the water was decanted followed by concentration. The residue was purified by flash chromatography (ethyl acetate/heptane 1:2) to give 0.413 g of the title compound (12%); Mp 168.5-169.5° C.; 1H-NMR (CDCl3): δ 3.83 (s, 3H), 7.00 (s, 1H), 7.14 (m, 3H), 7,23 (s, 1H), 7.32 (t, 1H), 7.43 ppm (t, 2H), 8.7 (br s, 1H). EI SP/MS: 335 (M+).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9]([C:10]([O:12]C)=[O:11])[O:8][C:7]([CH3:15])([CH3:14])[N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+:2]=[N-:3].[OH-].[K+]>CO>[N:1]([CH2:4][C@@H:5]1[C@@H:9]([C:10]([OH:12])=[O:11])[O:8][C:7]([CH3:15])([CH3:14])[N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1CN=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](CN=[N+]=[N-])[C@@H](C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Compound XXXVIII (0.064 g, 0.21 mmol) was dissolved in MeOH (1 mL) and a solution of 2M KOH (0.15 mL, 0.3 mmol) was added. The solution was stirred for 2 h at room temperature. The solvent was evaporated under reduced pressure and the resulting residue was treated with water and extracted with diethyl ether. The aqueous phase was separated, acidified with 1N HCl (pH=2) and extracted with EtOAc (3×15 mL). The organic phase was dried over Na2SO4 and evaporated producing (4R,5S)-4-(azidomethyl)-3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidine-5-carboxylic acid XXXIX (0.057 g, 0.19 mmol, 92%). ESIMS found for C12H20N4O5 m/z 301 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[OH:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH3:37])[CH2:25][C@H:24]5[OH:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1O
Product: CN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-hydroxy-1-methylpiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-hydroxypiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 270) and formaldehyde following General Procedure R.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:28])=[C:12]([N:16]2[CH2:21][CH2:20][CH:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.ClCCCl.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:28][C:11]1[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[CH2:17][CH2:18][CH:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:33](=[O:35])[CH3:34])[CH2:24][CH2:23]2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCC(C3CCNCC3)CC2)c1F
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)N1CCC(C2CCN(c3cccc(CO)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4,4′-bipiperidine (125 mg) and TEA (0.15 ml) were mixed with DCE (3 ml), and acetyl chloride (39 mg) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1 M TBAF/THF solution (0.6 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added an aqueous ammonium chloride solution and EtOAc, the organic layer was dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 1-{1′-[2-fluoro-3-(hydroxymethyl)phenyl]-4,4′-bipiperidin-1-yl}ethanone (84 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@H:7]([OH:9])[CH3:8])=[CH:3][CH:2]=1.C([Li])CCC.[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>C1COCC1.CCCCCC>[C:15]12([C:25]([O:9][C@@H:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH3:8])=[O:26])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C[C@@H](O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@H](OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccncc1
Yield: 88.1 %

Procedure:
The method followed that described in Example 1, but using (+)-(R)-1-(4-pyridyl)ethanol (369 mg, 3.0 mmol) in THF (12 ml), n-butyllithium (2.5 M, 1.2 ml, 3.0 mmol) in hexane, and 1-adamantanecarbonyl chloride (656 mg, 3.3 mmol) in THF (3 ml). Chromatography, on elution with petrol-ether-triethylamine 200:50:1, afforded the title compound (754 mg, 88%). [α]D +25.8° (c 1, CHCl3); IR νmax 1730 cm-1 ; 1H-NMR (CDCl3) δ1.50 (3H, d, J 6.6 Hz, CHCH3), 1.73 and 1.93 (12H, 2s, adamantyl CH2), 2.04 (3H, s, adamantyl CH), 5.80 (1H, q, J 6.6 Hz, OCH), 7.23 (2H, d, J 6.1 Hz, Py 3 and 5H), 8.58 (2H, d, J 6.1 Hz, Py 2 and 6H); MS m/z 285 (M+). By passing hydrogen chloride gas through a solution of the product in ether, the hydrochloride was obtained, m.p. 164°-166° C. Anal. Calcd: C, 67.17; H, 7.52; N, 4.35. Found: C, 67.58; H, 7.51; N, 4.36%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[C:13]([Mg]Br)#[C:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[C:13]#[C:14][CH3:15]
Reactant: CC#C[Mg]Br
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC1(O)C(=O)Nc2ccc(Br)cc21
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 5-bromoisatin (2.5 g, 11 mmol) in dry THF (100 cm3) at −10° C. under a nitrogen atmosphere was added 1-propynylmagnesium bromide (0.5 M in THF, 47 cm3,23.5 mmol). After 1 h, the mixture was poured into saturated ammonium chloride and extracted with EtOAc (×3), washed with brine, dried (MgSO4) and evaporated to afford 5-bromo-3-hydroxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (2.83 g, 10.6 mmol, 97%) which was used without further purification: (CDCl3) δ1.83 (s, 3H), 6.79 (d, 1H, J=8.0 Hz), 6.90 (s, 1H), 7.41-7.44 (m, 2H), 10.59 (s, 1H); MS ((−) ESI) m/z 264 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=1)#[CH:11]>C1(C)C=CC=CC=1>[CH3:20][N:19]([CH3:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12](/[CH:10]=[CH:11]/[B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]2)=[CH:13][CH:14]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: C#Cc1ccc(CN(C)C)cc1
Solvent: Cc1ccccc1
Product: CN(C)Cc1ccc(/C=C/B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 50 °C
Yield: 84.8 %

Procedure:
4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.20 mL, 8.23 mmol) was added to an argon-purged solution of 1-(4-ethynylphenyl)-N,N-dimethylmethanamine (262 mg, 1.65 mmol) and HRuCl(CO)(PPh3)3 (104.1 mg, 0.11 mmol) in toluene (9.0 mL). The resulting mixture was heated at 50° C. for 12 h. The product was extracted into Et2O (250 mL), and the organic layer was washed sequentially with water (3×20 mL) and brine (20 mL), dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography (silica gel, 50-100% CH2Cl2 in Et2O) gave (E)-N,N-dimethyl-1-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenyl)methanamine (402 mg, containing 20% pinacol impurity by 1H NMR, 68% yield). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8 Hz, 2H), 7.4 (d, 1H), 7.28 (d, 2H), 6.16 (d, 1H), 3.42 (s, 2H), 2.24 (s, 6H), 1.32 (s, 12H); MS ESI 288.0 [M+H]+, calcd for [C17H26BNO2+H]+ 288.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH3:23])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(F)c(F)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
3,4-Difluorophenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[S:28])=[CH:25][CH:24]=1>>[C:3]([C:2]([NH:1][C:27](=[S:28])[C:26]1[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:31][CH:30]=1)([CH3:20])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([O:15][C:16]([F:17])([F:18])[F:19])=[CH:14][C:8]2=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2ccc(OC(F)(F)F)cc2n1
Product: CC(C#N)(Cn1nc2ccc(OC(F)(F)F)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-trifluoromethoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile (100 mg, described in Example 30) and 4-trifluoromethylthiobenzoyl chloride (0.12 mL), the title compound was isolated as a white solid (142 mg, 83%). MS (ES): M/Z [M+H]=490. 1H NMR: (400 MHz, CHLOROFORM-d): 1.75 (s, 3H), 5.48 (d, J=13.4 Hz, 1H), 5.52 (d, J=13.3 Hz, 1H), 7.47 (d, J=10.6 Hz, 1H), 7.85-7.91 (m, 4H), 8.05 (br s, 1H), 8.12 (d, 1H, J=9.3 Hz) and 8.98 (br s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −57.43 (s, 3F) and −41.96 (s, 3F).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23](N(OC)C)=[O:24])=[N:15]1.[CH3:29][Mg+].[Br-]>C1COCC1>[C:23]([C:16]1[C:17](=[O:22])[C:18]([O:20][CH3:21])=[CH:19][N:14]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[C:2]=2[F:1])[N:15]=1)(=[O:24])[CH3:29]
Reactant: COc1cn(-c2cccc(-c3cnn(C)c3)c2F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cccc(-c3cnn(C)c3)c2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 1.67 h
Yield: 79.8 %

Procedure:
To a solution of 1-[2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl]-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (345 mg, 0.890 mmol) in THF (100 mL) was added MeMgBr (1.0 M in THF, 2.67 mL, 2.67 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 100 min. The reaction was quenched with saturated NH4Cl aqueous solution at −78° C. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (EtOAc/MeOH=100/0 to 70/30) to yield the title compound (243 mg, 80% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.51 (3H, brs), 3.81 (3H, s), 3.91 (3H, s), 7.38-7.46 (1H, m), 7.54-7.64 (1H, m), 7.86-7.95 (1H, m, J=15.0, 1.7 Hz), 7.98 (1H, s), 8.25 (1H, d, J=2.3 Hz), 8.58 (1H, d, J=1.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[C:18]([N+:15]([O-:17])=[O:16])[CH3:19])[CH:3]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1cccc(Br)c1)[N+](=O)[O-]

Procedure:
A suspension of 3-bromo-benzaldehyde (2.5 g, 13.5 mmol), ammonium acetate (1.09 g, 14.2 mmol), and nitroethane (250 mL) was heated to reflux overnight. Solvent removed under vacuum then residue partitioned between ethyl acetate and saturated sodium chloride. Concentrated organic purified on silica and isolated as a yellow oil. 1H NMR (CDCl3) s (3H, 2.44 ppm), m (2H, 7.35 ppm), m (2H, 7.55 ppm) s (1H, 8.00 ppm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[S:11])=[CH:5][CH:4]=1.[C:21]([C:26](O)=[O:27])#[C:22][C:23]([OH:25])=[O:24]>>[O:27]=[C:26]1[C:21](=[CH:22][C:23]([OH:25])=[O:24])[S:11][C:10](=[N:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:12]1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: COc1ccc(NC(=S)Nc2ccc(OC)cc2)cc1
Reactant: O=C(O)C#CC(=O)O
Product: COc1ccc(N=C2SC(=CC(=O)O)C(=O)N2c2ccc(OC)cc2)cc1
Yield: 65.7 %

Procedure:
Prepared by the method described in Example 1 from N,N'-bis(4-methoxyphenyl)thiourea (11.5 g, 40 mmoles) and acetylenedicarboxylic acid (4.6 g, 40 mmoles). Recrystallization from methanol gave the product (10.1 g), mp 184°-187° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N(Br)C(=O)C1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)(Cl)Cl.CCO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Cc1ccc(I)cc1F
Reactant: C1COCCN1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Fc1cc(I)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of 2-fluoro-4-iodotoluene (23.60 g, 0.10 mol) in CHCl3 (1000 mL) was added BPO (0.55 g, 2.27 mmol) and NBS (24.92 g, 0.14 mol) under N2. The reaction mixture was refluxed for 6 h, then cooled and filtered. The filtrate was concentrated in vacuo. The residue was added to a solution of morpholine (43.56 g, 0.50 mol) in EtOH (1000 mL) under N2. The resulting mixture was stirred at rt overnight, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a white solid (4.82 g, 15%).
Reaction SMILES: C(O[C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])C.C(N[N:18]([CH2:22][CH3:23])NCC)C>>[CH2:12]([N:13]([CH2:23][CH2:22][NH:18][C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH2:6][CH3:4])[CH3:11]
Reactant: CCOC(=O)C1CCC2CCC(=O)N21
Reactant: CCNN(CC)NCC
Product: CCN(CC)CCNC(=O)C1CCC2CCC(=O)N21
Temperature: 80 °C

Procedure:
A solution of hexahydro-5-oxo-1H-pyrrolizine-3-carboxylic acid ethyl ester (5.0 g, 0.0254 mol) in N,N-diethylaminoethylamine (23.2 g, 0.2 mol) is stirred at room temperature 24 hours and heated at 80° C. for 24 hours. The solution is concentrated at reduced pressure and distilled to yield N-[N,N-diethylamino-ethyl]hexahydro-5-oxo-1H-pyrrolizine-3-carboxamide
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N:15]([O-])=O.[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[N:15][NH:9][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Clc1ccc2[nH]nnc2n1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
6-Chloropyridine-2,3-diamine (Example 23, Step 1) (226 mg, 1.57 mmol) was taken up in warm water (6.3 ml). Sulfuric acid (0.26 ml, 4.72 mmol) was added, and the solution was cooled to −15° C. In a separate flask, sodium nitrite (119 mg, 1.73 mmol) was dissolved in 2 mL cold water. The sodium nitrite solution was added dropwise to the reaction mixture over 15 minutes. The mixture was allowed to stir at −15° C. for 1 hour, then filtered, and the yellow-brown precipitate was collected. The solid was recrystallized from water to yield the title compound as a yellow-brown solid. The filtrate from the separation was neutralized with aqueous sodium bicarbonate and extracted 3× with ethyl acetate. All organic fractions were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an additional portion of the title compound as a yellow-brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:25])[C:8]2[O:14][C:13]3[C:15]([Cl:22])=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:12]=3[CH2:11][S:10](=[O:23])[C:9]=2[CH:24]=1)=[O:4]>CN(C=O)C.[Ni]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:25])[C:8]2[O:14][C:13]3[C:15]([Cl:22])=[CH:16][C:17]([NH2:19])=[CH:18][C:12]=3[CH2:11][S:10](=[O:23])[C:9]=2[CH:24]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)Cc1cc([N+](=O)[O-])cc(Cl)c1O2
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)Cc1cc(N)cc(Cl)c1O2
Reaction time: 6 h

Procedure:
The solution of compound of Example 15c (3.7 g, 9.7 mmol) in DMF(100 mL) was added to a suspension of activated Raney Nickel (3.7 g) in DMF (10 mL) and was subjected to hydrogenation at 50 psi pressure at 25° C. for 6 h. The reaction mixture was filtered using celite bed and the solvent was removed. The crude product obtained was purified by column chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 2.5 g, (74%); 1H NMR (DMSO-d6, 300 MHz): δ 2.56 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 4.61 (q, 2H, CH2), 5.5 (s, 2H, NH2), 6.61 (s, 2H, Ar), 7.97 (s, 1H, Ar); MS: m/e (El) 351 (M+).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](Cl)[C:14](=[CH2:16])[CH3:15]>C(O)C>[CH3:15][C:14](=[CH2:13])[CH2:16][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=C(C)CCl
Agent: [Na]
Solvent: CCO
Product: C=C(C)CC(C(=O)OCC)C(=O)OCC
Reaction time: 2 h

Procedure:
Sodium (5.08 g.) was dissolved in dry ethanol (300 ml.). Diethyl malonate (35 g.) was added and the mixture was stirred for 2 hours. Methallyl chloride (20 g.) was added and the mixture was refluxed with stirring for 4 hours. The mixture was cooled, the solid filtered off and the solvent was removed in vacuo. 2N Hydrochloric acid solution was added and the mixture was extracted with diethyl ether. The ethereal extracts were washed with sodium hydrogen carbonate solution, water and then dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. Distillation gave diethyl 2-methyl-prop-2-enylmalonate as a colourless liquid (28.2 g. b.p. 120°-126° 20 mm.).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH:7]([CH3:10])[CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[CH2:11](O)[CH2:12][CH2:13][CH2:14][OH:15]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH:7]([CH3:10])[CH2:8][OH:9])(=[O:4])[O:5][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH3:2]
Reactant: CCP(=O)(O)CC(C)CO
Reactant: OCCCCO
Solvent: Cc1ccccc1
Product: CCP(=O)(CC(C)CO)OCCCCO
Yield: 77.9 %

Procedure:
498 g (3.0 mol) of ethyl(2-methyl-3-hydroxypropyl)phosphinic acid (produced as in Example 13) are at 80° C. dissolved in 400 ml of toluene and admixed with 594 g (6.6 mol) of 1,4-butanediol and esterified at about 100° C. in a distillation apparatus equipped with water trap during 4 h. On completion of the esterification the toluene is removed in vacuo to leave 557 g (78% of theory) of 4-hydroxybutyl ethyl(2-methyl-3-hydroxypropyl)phosphinate as colorless oil.