Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][CH:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[OH:6].C(N(CC)CC)C>ClCCl.CS(C)=O>[F:1][C:2]([F:18])([F:19])[CH2:3][CH2:4][C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[O:6]
Reactant: CCOC(=O)c1ccc(C(O)CCC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C(=O)CCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (+/−)-ethyl 4-(4,4,4-trifluoro-1-hydroxybutyl)benzoate (2.10 g, 7.60 mmol) in dichloromethane (28 ml), dimethyl sulfoxide (22 ml), and triethylamine (5.29 ml, 38.0 mmol) was cooled to 0° C. Sulfur trioxide pyridine complex (3.63 g, 22.8 mmol) was added in portions and the mixture stirred at 0° C. for 1 hour, then slowly raised to ambient temperature over 12 h. The reaction was quenched with water and diluted with diethylether. The aqueous layer was extracted with diethylether and the combined organic layers were washed with brine. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to affording the crude product as a solid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][C:15]=2[N:16]=1.[CH3:24][Si](C=[N+]=[N-])(C)C>CO.C1COCC1.CCCCCC>[CH3:24][O:22][C:21]([C:18]1[CH:19]=[CH:20][C:14]2[S:13][C:12]([S:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[Cl:1])=[N:16][C:15]=2[CH:17]=1)=[O:23]
Reactant: O=C(O)c1ccc2sc(Sc3ccc([N+](=O)[O-])cc3Cl)nc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc2sc(Sc3ccc([N+](=O)[O-])cc3Cl)nc2c1
Reaction time: 18 h
Yield: 100 %

Procedure:
To a 0.25M solution of 2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiazol-5-carboxylic acid (253), (1.38 g, 3.8 mmol) in 10% MeOH in THF was added a 2M solution of (trimethylsilyl)diazomethane in hexane, obtained from Aldrich, (2.1 mL, 4.18 mmol) and the resulting solution was allowed to stir for 18 hours. The crude reaction mixture was concentrated under vacuum to yield 1.4 g (100%) of ester 254 which was taken on without further purification.
Reaction SMILES: C(OC([N:11]1[C@H:15]([C:16]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][S:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[C:19]([NH:18][C:16]([C@@H:15]1[CH2:14][S:13][CH2:12][NH:11]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 3.2 g of 3-(benzyloxycarbonyl)-N-tert.butyl-4(R)-thiazolidinecarboxamide and 10 ml of 32% (w/w) hydrogen bromide in glacial acetic acid was stirred at room temperature for 2 hours. The resulting solution was poured into diethyl ether and the precipitated hydrobromide salt of the product was filtered off, washed with diethyl ether and then dissolved in water. The solution was made alkaline by the addition of 1M sodium hydroxide solution and extracted twice with dichloromethane. The combined dichloromethane extracts were washed with water, dried over anhydrous sodium sulphate, filtered and evaporated to give 1.57 g of N-tert.butyl-4(R)-thiazolidinecarboxamide as a crystalline solid of melting point 68°-71° C.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=1)#N.[CH2:18]([OH:20])[CH3:19]>>[CH3:14][C:12]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=[C:8]([C:6]([O:20][CH2:18][CH3:19])=[O:2])[CH:13]=1
Reactant: CCO
Reactant: Cc1cc(C#N)ncc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C)c([N+](=O)[O-])cn1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To concentrated sulfuric acid (45 mL) was added ethanol (100 mL) under ice-cooling, followed by adding 2-cyano-4-methyl-5-nitropyridine (3.54 g), and the reaction vessel was equipped with a reflux condenser, and the mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice, and the resulting mixture was extracted with diethyl ether. The water layer was extracted with methylene chloride. The extracts were combined, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (3.23 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CCCCCC.C([Li])CCC.[B:32](OC)([O:35]C)[O:33]C.Cl>C1COCC1>[C:7]1([N:6]2[C:5]3[CH:13]=[CH:14][C:2]([B:32]([OH:35])[OH:33])=[CH:3][C:4]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
Into a solution of 19.6 g (60.7 mmol) of 3-bromo-9-phenylcarbazole, prepared in Step 1 of the Embodiment 2, in THF (100 mL) was added dropwise 66.8 mL (42.3 mmol) of an n-butyllithium hexane solution (1.58 mol/L) at −78° C. under nitrogen, which was followed by stirring for 3 hours at the same temperature. Thereafter, 13.5 mL (140 mmol) of trimethyl borate was added, and stirring was continued for 24 hours while gradually raising the reaction temperature to room temperature. 200 mL of 2.0 mol/L hydrochloric acid was added to the solution, and additional stirring was conducted for 1 hour at room temperature. After the solution was extracted with ethyl acetate, the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated. The resulting solid was recrystallized with a mixed solvent of chloroform and hexane, giving 10.2 g of 9-phenylcarbazole-3-ylboronic acid as white powder in 58% yield.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:20]2[CH:41]=[C:42]([C:45]([F:48])([F:47])[F:46])[CH:43]=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([N:25]([C:1](=[O:3])[CH3:2])[CH2:26][C:27]2[CH:28]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=2)[C:20]2[CH:41]=[C:42]([C:45]([F:48])([F:46])[F:47])[CH:43]=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2ccc(C(F)(F)F)cc21
Reaction time: 2 h
Yield: 83 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (0.1 g, 0.4 mmol) followed by titanium isopropoxide (1.0 mL) to 5-Oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.13 g, 0.4 mmol) and stir at room temperature overnight. Dilute the mixture with 5 mL of Methanol and add sodium borohydride (0.8 mmol). Stir the suspension at room temperature for 30 min then dilute with water (20 mL) and ethyl acetate (20 mL). Filter the resulting emulsion through celite and wash with ethyl acetate (3×20 mL). Separate the organics, dry over sodium sulfate, and filter. Remove the solvent under vacuum to afford (+/−)-t-butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate crude (0.2 g, MS (ES+): 557 (M+H)). Without further purification, add acetyl chloride (0.8 mmol) and pyridine (0.8 mmol) to a solution of (+/−)-t-butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in dichloromethane. After stirring for 2 h remove solvent under vacuum and chromatograph over silica gel using ethyl acetate/hexane (5-40%) to elute. This affords the title compound as an oil (0.2 g, 83%) which foams under vacuum: MS (ES−): 597 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH:8]=[O:9].[C:17]([O-])(O)=[O:18].[Na+].BrBr>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[NH:10][C:5]2=[N:6][C:7]=1[C:8]([O:18][CH3:17])=[O:9]
Reactant: CCCCc1nc2nc(C=O)c(Br)cc2[nH]1
Reactant: O=C([O-])O
Agent: BrBr
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCc1nc2cc(Br)c(C(=O)OC)nc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
0.69 g (2.45 mmole) of the compound obtained in step 7 of Example 1 was dissolved in 10 ml of MeOH--H2O (9:1) and to the resulting solution was added 4.12 g (49 mmole) of NaHCO3. The resultant was stirred until NaHCO3 was dissolved and thereto was added 2.0 ml (4.9 mmole) of Br2. The resulting solution was stirred for 1 hour at room temperature and extracted with a mixture of water and ethyl acetate. The organic layer was dried over MgSO4 and evaporated under reduced pressure to obtain 0.75 g of the title compound (quantitative).
Reaction SMILES: [CH3:1][O:2][P:3]([CH3:7])(=[O:6])[O:4][CH3:5].[Li]CCCC.[C:13]([O:17][C:18]([N:20]1[C@H:24]([C:25]([O-])=[O:26])[CH2:23][O:22][C:21]1([CH3:29])[CH3:28])=[O:19])([CH3:16])([CH3:15])[CH3:14].CCOC(C)=O>C1COCC1.CCO>[C:13]([O:17][C:18]([N:20]1[C@H:24]([C:25](=[O:26])[CH2:7][P:3]([O:4][CH3:5])([O:2][CH3:1])=[O:6])[CH2:23][O:22][C:21]1([CH3:29])[CH3:28])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)[O-])COC1(C)C
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COP(=O)(CC(=O)[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C)OC
Temperature: -75 °C
Yield: 70 %

Procedure:
Dimethylmethylphosphonate (2.3 ml, 21 mmol, 210 mol-%) was dissolved in 10 ml of THF and cooled to -85° C. (internal temp. -75° C.). To this solution was added 14 ml (1.6M, 21 mmol, 210 mol-%) of n-BuLi in hexanes. The reaction mixture was allowed to warm to -25° C. for 1 hour and then cooled back to -85° C. (internal temp. <-75° C.) after which 2.6 g (10 mmol, 100 ml-%) of methyl ((S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4oxazolidine carboxylate was dissolved in 5 ml of THF and cooled to -85° C. (internal temperature <-75° C.). This solution was cannulated onto the anion at such a speed that the internal temperature stayed <-75° C. at all times. After the addition the reaction mixture was allowed to warm to 0° C. very slowly and then it was quenched with 5 w-% citric acid. The pH was adjusted to 3 with sat. citric acid and the reaction mixture was extracted several times with ethyl acetate (EtOAc). Organic phases were washed with brine, combined, dried over Na2SO4 and the solvents were removed in vacuo. The product can be crystallized if necessary from iso-octane. An analytical sample was purified by flash chromatography using 20% EtOAc in hexanes to remove the traces of starting material and then as a stepgradient with 100% EtOAc to remove the excess of dimethylmethylphosphonate to yield 70% of pure 3. Rf, 100% EtOAc: 0.28. mp. 86°-7° C. 1H NMR (250 MHz, CDCl3) δ:1.30 (s, 3 H, major rotamer) , 1.36 (s, 3 H, minor rotamer) , 1.40 (s, 3 H both rotamers), 1.51 (s, 3 H, major rotamer), 1.55 (s, 3 H minor rotamer), 3.06 (d, 2 H, major rotamer, 2J(HP)=20 Hz), 3.10 (d, H, minor rotamer, 2H(HP)=20 Hz), 3.68 (d, 6 H, 3J(HP)=11,2 Hz), 3.91 (dd, 1 H, minor rotamer, J=3.6 Hz, <0.5 Hz), 3.93 (dd, 1 H, major rotamer, J=3.6 Hz, <0.5 Hz), 4.05 (m, 1 H, both rotamers) , 4.38 (m, 1 H, major rotamer) , 4.48 (m, 1 H, minor rotamer). Rotameric ratio is 2:1 at 20° C. 13C NMR (50 MHz, CDCl3) δ:23.7 (CH3), 25.0 (CH3), 28.0 (CH3), 52.7 (CH3), 65.0 (c), 65.1 (CH2), 89.8 (c), 94.4 (CH2), 95.(C), 150.9 (C=O), 199.0 (C=O) . Anal. Calcd. C 47.86: H 7.46; N 3.99; Found C 48.11; H 7.70; N 4.26. α20 =-40.1(c=14.0, EtOH).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].CC(O)=O.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:13]([NH:20][CH2:2][CH2:1][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=Cc1ncccn1
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(CNCCc2ncccn2)cc1

Procedure:
To a solution of 2-vinylpyrimidine (1.55 g, 14.6 mmol) in EtOH (15 mL) at room temperature was added AcOH (2.0 mL) and benzylamine (3.14 g, 29.3 mmol) (3.2 mL). The reaction mixture was heated to reflux for 18 h, and concentrated. Diluted with EtOAc, washed with 5 M NaOH (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 10% MeOH in DCM) gave N-benzyl-2-(pyrimidin-2-yl)ethanamine.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:32])[CH2:14][CH:15]([NH:20][C:21](=[O:31])[C@@H:22]([N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=[O:30])[CH3:23])[C:16](=[O:19])[CH2:17][F:18])(C)(C)C>ClCCl>[F:18][CH2:17][C:16](=[O:19])[CH:15]([NH:20][C:21](=[O:31])[C@@H:22]([N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=[O:30])[CH3:23])[CH2:14][C:13]([OH:32])=[O:12]
Reactant: C[C@@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF)n1ccccc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C(=O)NC(CC(=O)O)C(=O)CF)n1ccccc1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (2 ml) was added to a stirred ice cold solution of 5-Fluoro-4-oxo-3-[(S)-2-(2-oxo-2H-pyridin-1-yl)-propionylamino]-pentanoic acid tert-butyl ester (115 mg, 0.32 mmol) in anhydrous dichloromethane (2 ml). The mixture was stirred at 0° C. for 0.5 h then at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and then the residue was redissolved in dry dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The gum was lyophilized twice from HPLC grade water to afford the title compound as an off white solid: IR (solid) 1789, 1730, 1654 cm−1; 1H NMR (400 MHz, DMSO) δ 1.4-1.6 (3H, m), 2.5-2.9 (2H, m), 4.2-4.7 (2H, m), 5.0-5.5 (2H, m), 6.2-6.3 (1H, m), 6.3-6.5 (1H, m), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.9 (1H, m); 13C NMR (100 MHz, DMSO) δ 17.15, 17.27, 17.61, 17.87, 17.94, 33.50, 33.57, 35.02, 35.23, 35.31, 52.69, 53.08, 53.31, 53.42, 53.47, 53.79, 53.91, 54.49, 54.85, 81.55, 81.92, 83.31, 83.68, 83.95, 84.07, 85.72, 85.84, 105.87, 106.07, 106.19, 119.67, 119.86, 120.26, 137.05, 137.31, 137.36, 137.40, 137.43, 140.60, 140.65, 140.74, 140.85, 162.14, 162.18, 162.28, 162.32, 171.25, 171.48, 171.62, 171.69, 172.55, 172.63, 173.63, 173.67, 174.52, 203.04, 203.18, 203.28, 203.42; MS (FAB+ve, HR) Calculated for C13H16FN2O5 (MH+) 299.1043, found 299.1045.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:13][C:10]1[N:11]=[CH:12][C:7]([CH2:6][N:1]=[N+:2]=[N-:3])=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(CCl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(CN=[N+]=[N-])cn1
Reaction time: 1 h
Yield: 69.7 %

Procedure:
NaN3 (11.2 g, 172 mmol) was added to a solution of the 5-(chloromethyl)-2-methylpyridine (12.2 g, 86.2 mmol) in dimethylformamide (120 ml) while cooling on ice and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was poured into semi-saturated aqueous sodium hydrogencarbonate, extraction was performed with ethyl acetate and the extract was washed with water and saturated aqueous NaCl. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (8.9 g, 26%, two steps) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[S:16][CH3:17].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:6]([C:7]([Cl:27])=[O:8])=[CH:5][C:4]=1[S:16][CH3:17]
Reactant: COc1c(SC)cc(C(=O)O)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(SC)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 4-methoxy-3-methylsulfanyl-5-trifluoromethylbenzoic acid (277 mg), toluene (7 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.12 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (f).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][S:10]C)=[CH:4][N:3]=1.[N:12]#[C:13][NH2:14].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[F:8][C:7]1[CH:6]=[C:5]([CH2:9][SH:10]=[N:14][C:13]#[N:12])[CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: N#CN
Reactant: CSCc1cnc(Cl)c(F)c1
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CN=[SH]Cc1cnc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a stirred solution of 2-chloro-3-fluoro-5-methylthiomethylpyridine (1.7 g, 8.9 mmol) and cyanamide (3.7 g, 8.9 mmol) in THF (15 mL) cooled to 0° C. was added iodobenzene diacetate (2.86 g, 8.9 mmol) in one portion and the resulting mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h. The solvent was removed in vacuo and the resulting mixture was purified on silica gel using 60% acetone in hexane to give 1.828 g of [1-(5-fluoro-6-chloropyridin-3-yl)methyl]-λ4-sulfanylidenecyanamide as an off-white solid in 89% yield. LC-MS calcd. for C8H7ClFN3S [M+1]+: 232.69. Found: 232.04.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH2:10]([N:17]1[CH2:34][CH2:33][C:20]2([C:24](=[O:25])[N:23]([C:26]3[CH2:27][O:28][C:29](=[O:32])[C:30]=3[CH3:31])[CH2:22][CH2:21]2)[CH:19](O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH2:10]([N:17]1[CH2:34][CH2:33][C:20]2([C:24](=[O:25])[N:23]([C:26]3[CH2:27][O:28][C:29](=[O:32])[C:30]=3[CH3:31])[CH2:22][CH2:21]2)[CH:19]([F:7])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1=C(N2CCC3(CCN(Cc4ccccc4)CC3O)C2=O)COC1=O
Solvent: ClCCl
Product: CC1=C(N2CCC3(CCN(Cc4ccccc4)CC3F)C2=O)COC1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a flask charged with DCM (5 mL) and a stir bar was added DAST (0.092 mL, 0.69 mmol) at −78° C., which was followed by addition of 8-benzyl-6-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-35, Step C) (165 mg, 0.46 mmol) in DCM. The mixture was stirred at −78° C. for 15 minutes, and then allowed to warm up to RT slowly. The reaction was quenched with aq NaHCO3 and after 3 hours at RT it was extracted with DCM, dried over sodium sulfate, and purified by MPLC with hexane and EtOAc. Two spots were collected with the desired molecule weight in the ratio of 1:4. The less polar compound, which is the minor isomer, was designated as Isomer A, and the more polar major isomer was designated as Isomer B. LCMS: m/z 359 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:23](OCC)=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:7]=1C(OCC)=O.[H-].[Na+].[N:31]1C=NC=N[CH:32]=1.C[N:38]([CH3:41])[CH:39]=[O:40]>>[O:40]=[C:39]1[NH:38][CH:41]=[CH:1][C:2]2[NH:3][C:4]3[CH:28]=[CH:32][NH:31][C:23](=[O:24])[C:5]=3[CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[C:7]1=2
Reactant: c1ncncn1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: O=c1[nH]ccc2c1C(c1ccccc1C(F)(F)F)c1c(cc[nH]c1=O)N2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 39.7 g (0.1 mole) diethyl 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxylate in 250 ml dimethylformamide is added dropwise, under an atmosphere of nitrogen, to a suspension of 6.0 g (0.2 mole) sodium hydride (80% in oil) in 100 ml dry dimethylformamide. After cessation of the evolution of gas, the reaction mixture is further stirred for 10 minutes at ambient temperature and subsequently 16.2 g (0.2 mole) s-triazine in 50 ml dimethylformamide are added dropwise thereto. The reaction mixture is stirred for 16 hours at 105° C. and, after cooling, evaporated in a vacuum. The residue is taken up in 200 ml ethanol and the crystals which separate out after stirring in an ice bath for several hours are filtered off. The mother liquor contains, as by-product, the ethyl (±)-1,4,5,6-tetrahydro-2-methyl-5-oxo-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate already described in German Pat. No. 33 27 650. The crystals are placed into an extraction column and extracted with methanol for 24 hours. After cooling, from the methanol solution there crystallize 1,2,5,8,9,10-hexahydro-1,9-dioxo-10-(2-trifluoromethylphenyl)-pyrido[4,3-b][1,6]naphthyridine in the form of pale beige crystals; mp 350° C. (dec).
Reaction SMILES: [CH2:1](N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([CH2:22][C:23]([O:25]CC)=O)#N.C(OCC)(=O)CC(C)=O.[NH:37]1CCC[CH2:39][CH2:38]1.Cl>CO.CN(C)C=O>[CH2:1]([C:22]1[C:23](=[O:25])[NH:37][CH:38]=[CH:39][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC#N
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: CO
Solvent: CCOC(=O)CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCc1ccc[nH]c1=O
Temperature: 120 °C
Yield: 65.7 %

Procedure:
Into a 2 liter Erlenmeyer flask equipped with magnetic stirring was charged stearylamine (118 g, 0.44 mol; obtained from Sigma-Aldrich) and ethyl cyanoacetate (ECA, 45.2 grams, 0.4 mol). The mixture was heated to 120° C. for 90 minutes, after which ethyl acetoacetate (EAA, 114 grams, 0.88 mol), piperidine (PIP; 70 grams, 0.82 mol), and dimethylformamide (DMF; 140 milliliters) were added. The mixture was heated to 120° C. for 4 hours. The mixture was then allowed to cool to room temperature and was poured slowly into well stirred methanol (1,200 milliliters), which contained concentrated hydrochloric acid (100 milliliters). The resulting suspension was allowed to stir for 10 minutes, and was then filtered and washed with 3×200 milliliter portions of methanol. The resulting solid was oven dried at 60° C. to give 91.3 grams of a beige powder at 57 percent yield.
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:17]([NH:20][CH2:21][C:22]([CH3:25])([NH2:24])[CH3:23])([CH3:19])[CH3:18].C(O)C>>[CH3:23][C:22]1([CH3:25])[CH2:21][N:20]([CH:17]([CH3:19])[CH3:18])[C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:24]1
Reactant: CCCCCCCCCCCC(=O)OCC
Reactant: CC(C)NCC(C)(C)N
Solvent: CCO
Product: CCCCCCCCCCCC1=NC(C)(C)CN1C(C)C
Yield: 56.8 %

Procedure:
22.84 g. (100 mmoles) of ethyl dodecanoate and 15.34 g. (118 mmoles) of N1 -isopropyl-2-methyl-1,2-propanediamine was heated at 130°-230° C. until approximately 100 mmoles of ethanol was collected. Toluene was then cautiously added and the heating was continued until no more water separated. The solution was acidified, the aqueous layer was separated and basified with NaOH. This was extracted with ethyl acetate, the organic extract was dried and concentrated. The oil was distilled at 150°-152° C./1.2 mm to give 16.74 g (58%) of product.