Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:29][C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C.[NH4+].[Cl-].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O.CCOC(C)=O>[CH3:28][O:27][C:24]1[N:23]=[CH:22][C:21]([CH2:20][NH:19][C:18]2[C:13]3[CH:12]=[C:11]([C:8]4[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=4)[NH:29][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(-c2cc3c(NCc4ccc(OC)nc4)ncnc3[nH]2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3[nH]c(-c4ccc(CO)cc4)cc23)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 g (12 mMol) of 4-[4-(6-methoxy-pyridin-3-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin -6-yl]-benzoic acid ethyl ester in 200 ml of THF is cooled to −10° C. Then 80 ml of a 1 N solution of di-isobutyl-aluminium hydride in THF are added dropwise. After stirring for 3 h at RT, 200 ml of THF and 100 ml of EtOAc are added, followed by 10 ml of a 10%-solution of NH4Cl in water. After 30 min vigorous stirring, 20 g of Na2SO4 are added, then the mixture is filtered through Celite. Concentration of the filtrate, stirring in methanol and filtration gives the title compound; MS-ES+: (M+H)+=362.
Reaction SMILES: BrC([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)C.[C:18]([O:24]CC)(=[O:23])[CH2:19][C:20]([CH3:22])=O.[OH-].[K+].Cl>O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([CH:20]([CH3:22])[CH2:19][C:18]([OH:24])=[O:23])=[CH:5][CH:6]=1
Reactant: CC(Br)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 2-[1-(2',4'-difluoro-4-biphenylyl)ethyl]-butan-3-one acid ethyl ester, obtained by reacting 4-(1-bromoethyl)-2',4'-difluorobiphenyl with ethyl acetoacetate, and 15 ml. of 50% KOH are stirred for 45 minutes at 90° under N2. The mixture is cooled, diluted with water and brought to pH 10 with HCl. The reaction mixture is washed with ether and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:10][C:6]=2[CH:7]=[CH:8]1
Reactant: C1CCNCC1
Reactant: Brc1ccc2occc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1cc2cc(N3CCCCC3)ccc2o1
Temperature: 120 °C
Yield: 26.8 %

Procedure:
5-bromobenzofuran (2 g, 10 mmol), piperidine (1.2 mL, 12 mmol), Pd(dppf)Cl2 (245 mg, 0.3 mmol), dppf (250 mg, 0.45 mmol) and sodium tert-butoxide (1.44 g, 15 mmol) was mixed in toluene (10 mL). The mixture was purged with N2 gas for 3-5 min and heated at 120° C. for 30 min under microwave irradiation (Personal Chemistry Emrys™ Optimizer microwave reactor). Upon completion of the reaction, the reaction mixture was directly loaded on silica gel column and purified on ISCO system (<2% EtOAc in hexanes) to give 0.539 g desired product (27% yield): ESI-MS: 202.3 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.40 (d, 1H), 7.15 (s, 1H), 7.00 (d, 1H), 6.65 (s, 1H), 3.10 (m, 4H), 1.70 (m, 4H), 1.48 (m, 2H). Note: the title compound appeared to be very volatile. The evaporation of solvent should be carried out very carefully.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[C:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:9]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17]1[CH:18]=[CH:19][C:14]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=1)#[N:10]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: N#CCc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred mixture containing 5.88 g (0.03 mol) of (2-bromo-phenyl)-acetonitrile, 4.978 g. (0.03 mol) of 4-carboxyphenylboronic acid, 8.29 g (0.06 mol) of potassium carbonate and 0.52 g of dichlorobis(triphenylphosphine)palladium(II) in 46 mL of water and 25 mL of 1,4-dioxane was heated under reflux for two hours in an atmosphere of nitrogen. The reaction mixture was allowed to cool to room temperature and filtered. The dioxane was removed in vacuo and the residue diluted with 100 mL of water and then acidified with 20% hydrochloric acid. The crude product (1.2g) was recrystallized from ethanol to give a solid, m.p. 218-220° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[C:23]([F:28])[C:22]=2[F:29])[N:13]=1)(C)(C)C.[CH3:31][O:32][C:33]1[N:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=1>>[NH2:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH:27][C:39]([C:36]3[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][N:37]=3)=[O:40])[CH:24]=[C:23]([F:28])[C:22]=2[F:29])[N:13]=1
Reactant: COc1cnc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Product: COc1cnc(C(=O)Nc2cc(F)c(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)cn1

Procedure:
Synthesized from tert-butyl[(4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-methoxypyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3+MeOD) δ ppm 2.83 (dd, J=13.9, 3.8 Hz, 1 H), 3.14 (dd, J=13.9, 3.0 Hz, 1 H), 3.29-3.39 (m, 1 H), 3.87 (d, J=8.3 Hz, 1 H), 4.04 (s, 3 H), 4.60 (d, J=8.3 Hz, 1H), 4.67 (quin, J=6.3 Hz, 1 H), 7.11-7.21 (m, 1 H), 8.03 (ddd, J=11.6, 6.9, 2.7 Hz, 1H), 8.15 (d, J=1.3 Hz, 1 H), 8.96 (d, J=1.3 Hz, 1 H)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[CH:7]([CH3:10])[C:8]#[CH:9].C(=O)([O-])[OH:13].[Na+]>CC(C)=O.O>[OH:1][CH:5]1[CH:4]=[CH:3][C:2](=[O:13])[CH:6]1[CH:7]([CH3:10])[C:8]#[CH:9]
Reactant: C#CC(C)C(O)c1ccco1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C#CC(C)C1C(=O)C=CC1O
Reaction time: 48 h
Yield: 52 %

Procedure:
1-(2-Furyl)-2-methyl-3-butyn-1-ol (15 g, 0.1 mole) was dissolved in a 2:1 mixture (150 ml) of acetone and water in a reactor, and p-toluenesulfonic acid (3 g) was dried. Thereafter, reaction was carried out at 50° to 60° C. for about 48 hours with stirring. After completion of the reaction, the reaction solution was cooled and neutralized with addition of a saturated aqueous solution (30 ml) of sodium hydrogen carbonate, followed by extraction with a solvent. The extrect was washed with water, dried and concentrated. The residue obtained was distilled under reduced pressure to obtain 7.8 g (yield, 52%) of pure (±)-3-hydroxy-2-(1-methyl-2-propynyl)-4-cyclopenten-1-one having a boiling point of 110°-115° C./3 mmHg.
Reaction SMILES: [C:1]([CH:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[OH-].[NH4+]>O1CCOCC1.[Ni].[Pd]>[NH2:2][CH2:1][CH:3]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:17]=1)[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C#N)Cc1ccc(-c2ccccn2)cc1
Agent: [Ni]
Agent: [Pd]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(CN)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of tert-butyl 2-cyano-3-(4-(pyridin-2-yl)phenyl)propanoate (150 mg, 0.486 mmol), Raney 2800 nickel (slurry in water) (0.486 mmol), Pd/C (51.8 mg, 0.049 mmol) and ammonium hydroxide (1.894 ml, 48.6 mmol) in dioxane (10 ml) was stirred at room temperature under H2 for 3 hours. The reaction mixture was filtered, and the filtrate was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound. LCMS (condition B): 313.3 (M+1); retention time=0.54 min.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[CH:14][C:15](=O)[NH:16][N:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].P(Br)(Br)([Br:21])=O>C1(C)C=CC=CC=1>[Br:21][C:15]1[N:16]=[N:17][C:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(=O)[nH]n2)CC1
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(Br)nn2)CC1
Temperature: 68 °C
Reaction time: 2 h

Procedure:
24.8 g of 6-(trans-4-pentylcyclohexyl)-3(2H)-pyridazinone (prepared according to Example 2) and 150 ml of toluene were suspended in a sulphonation flask under nitrogen. Subsequently, there was added dropwise within 7 minutes a solution of 11.5 g of phosphorus oxybromide, the temperature rising from 17° C. to 30° C. and a viscous light brown mass resulting. The mixture was treated with 30 ml of toluene and then heated slowly to 68° C., whereby it became dark green in colour. After 2 hours, a solution of 5.7 g of phosphorus oxybromide was added dropwise at 68° C. within 10 minutes. The mixture was heated to reflux temperature and once more treated with a solution of 7.4 g of phosphorus oxybromide. After 6 hours, the mixture was poured into 400 ml of ice/water and extracted six times with 250 ml of methylene chloride each time. The organic phases were washed with 400 ml of 5% sodium hydrogen carbonate solution, subsequently combined, dried with sodium sulphate and concentrated at 40° C. on a rotary evaporator. Column chromatography on silica gel with ethyl acetate/hexane (1:1) as the eluant gave 24.81 g of crude product. Crystallization from 75 ml of ethyl acetate/hexane (2:1) and working-up of the mother liquor finally yielded a total of 21.7 g of 3-bromo-6-(trans-4-pentylcyclohexyl)pyridazine as white crystals of melting point 101°-103° C.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[CH3:22])C(=O)C)=O)(C)(C)C.Cl.[C:28]([C:30]1[CH:43]=[CH:42][C:33]([CH2:34][N:35]2[C:39](C=O)=[CH:38][N:37]=[CH:36]2)=[CH:32][CH:31]=1)#[N:29].C([BH3-])#N.[Na+]>CCOC(C)=O.CO.C1COCC1.C(O)(=O)C>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([CH2:34][N:35]2[C:39]([CH2:6][NH:8][C@@H:9]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][NH:11][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=3[CH3:22])=[CH:38][N:37]=[CH:36]2)=[CH:42][CH:43]=1)#[N:29]
Reactant: CCCC[C@@H](CN(C(C)=O)c1cccc(C)c1C)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCC[C@@H](CNc1cccc(C)c1C)NCc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Through a solution of the product from Step I (533 mg, 1.47 mmol) in 20 mL of EtOAc at 0° C. was bubbled HCl gas. The saturated solution was warmed to room temperature and stirred for 40 minutes, then concentrated in vacuo. To a solution of this amine salt in 6 mL of 1:1 MeOH/THF at 0° C. was added the aldehyde from Step E (325 mg, 1.54 mmol) and 0.05 mL of acetic acid. After one hour, sodium cyanoborohydride was added (97 mg, 1.54 mmol), and the solution was allowed to warm to room temperature overnight. After ~16 hours, the reaction was poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2 SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (1-2% MeOH/CHCl3). A portion of this was taken up in EtOAc/Et2O and treated with excess HCl gas, then stripped to provide the titled compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[S:16][C:17]([NH:19][C:20]([N:22]3[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]3)=[O:21])=[N:18][C:11]=12.C(N(CC)C(C)C)(C)C.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][C:39]=1[C:46]([F:49])([F:48])[F:47].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CO.C(OCC)C.C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[S:16][C:17]([NH:19][C:20]([N:22]3[CH2:26][CH2:25][CH:24]([NH:27][CH2:42][C:41]4[CH:44]=[CH:45][C:38]([F:37])=[C:39]([C:46]([F:49])([F:47])[F:48])[CH:40]=4)[CH2:23]3)=[O:21])=[N:18][C:11]=12
Reactant: COc1ccnc2sc(NC(=O)N3CCC(N)C3)nc12
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccnc2sc(NC(=O)N3CCC(NCc4ccc(F)c(C(F)(F)F)c4)C3)nc12
Yield: 10.4 %

Procedure:
A suspension of the trifluoroacetic acid salt of 3-Amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-b]pyridine-2-yl)-amide (160 mg, 0.39 mmol) in methanol was treated with N,N-diisopropylethylamine (0.28 mL, 1.57 mmol). Stir the reaction at 25° C. for 30 min. The methanol is then removed in vacuo. 4-fluoro-3-(trifluoromethyl)benzaldehyde (0.08 mL, 0.59 mmol) and toluene are then added to the flask and the resulting mixture was stirred at 60° C. for 1 h and was then concentrated in vacuo. This procedure was repeated until the reaction mixture became homogenous when dissolved in toluene. After the final concentration to remove toluene, the reaction mixture was diluted with dichloroethane (15 mL) and then was treated with acetic acid (94 mg) and sodium triacetoxyborohydride (250 mg, 1.18 mmol). The resulting reaction mixture was allowed to stir at 25° C. overnight. At this time, the reaction mixture was poured into 1N NaOH and extracted into methylene chloride. The organics were washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98:2 methylene chloride/methanol) afforded a colorless oil. The oil was dissolved in diethyl ether and then was concentrated in vacuo to afford 3-(4-Fluoro-3-trifluoromethyl-benzylamino)-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-b]pyridin-2-yl)-amide (19 mg, 25%) as a white solid. LRMS for C20H19F4N5O2S (M+H)30 at m/z=469. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[NH:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.C([Li])CCC.Cl[P:24]([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26]>>[CH:25]([P:24]([CH:28]([CH3:30])[CH3:29])[N:17]=[C:10]([NH:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:27])[CH3:26]
Reactant: N=C(NCCN1CCOCC1)c1ccccc1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Product: CC(C)P(N=C(NCCN1CCOCC1)c1ccccc1)C(C)C

Procedure:
Procedure as described for NP Amidine XVII using the following amounts: 0.956 g of N1-(2-morpholinoethyl)benzamidine (Amidine XV, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (1.71 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([C:18](=O)[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[CH:30]=[CH:29][CH:28]=[N:27]4)[CH:21]=3)[CH2:14][CH2:13]2)[N:3]=1.Cl>O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[CH:30]=[CH:29][CH:28]=[N:27]4)[CH:21]=3)[CH2:14][CH2:13]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)Cc4cccc(-n5cccn5)c4)CC3)cccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CCN(CCc4cccc(-n5cccn5)c4)CC3)cccc2n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
A 1M tetrahydrofuran solution of borane-tetrahydrofuran complex (3 eq) was added to a stirred solution of 2-methyl-5-(4-{[3-(1H-pyrazol-1-yl)phenyl]acetyl}-1-piperazinyl)quinoline (E97) (1 eq) in tetrahydrofuran at room temperature under an inert atmosphere. The solution was heated to 60° C. for 3 hrs. An aqueous 3N solution of HCl was added and the solution was stirred at room temperature for 12 hrs. The solvent was removed under reduced pressure. The crude material was purified by SCX cartridge affording the title compound in 52% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C>[C:12]1([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccc(-c2ccccc2)c1

Procedure:
1.00 g (4.65 mmol) of methyl 3-bromobenzoate, 0.60 g (4.88 mmol) of phenylboronic acid, 161 mg (3 molar %) of tetrakistriphenylphosphine palladium and 2.0 g (18.6 mmol) of sodium carbonate were heated under reflux in 24 ml of a solvent mixture of toluene, ethanol and water (2/1/1) for 2 hours. The mixture was filtered through Celite, then after-treated by an ordinary method and purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[C:4]([CH3:18])[CH:3]=1.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].C1CCN2C(=NCCC2)CC1>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:12])=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(I)ccc1Nc1cnccc1C(=O)O
Reactant: CS(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1Nc1cnccc1C(=O)NS(C)(=O)=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
3-[(4-Iodo-2-methylphenyl)amino]isonicotinic acid (example 3) (50 mg, 0.141 mmol) was dissolved in 4 ml dry THF followed by the addition of 1,1″-carbonyldiimidazole (CDI) (0.311 mmol, 50 mg), methanesulfonamide (0.169 mmol, 16.1 mg) and DBU (0.169 mmol, 26 mg). The mixture was stirred for 16 h at 40° C. and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 20.3 mg (47 μmol; 33% yield) of pure desired product. LC-MS (method III): rt=2.74 min; m/z [M+H]+ 432.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([N:14]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:15]([C@@H:17]([NH:19]C(OC(C)(C)C)=O)[CH3:18])=[O:16])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:14]2[C:15](=[O:16])[C@H:17]([CH3:18])[NH:19][C:3](=[O:2])[C@H:4]2[CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)[C@@H](COCc1ccccc1)N(Cc1ccc(F)cc1)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1NC(=O)[C@@H](COCc2ccccc2)N(Cc2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)-N-(((1S)-1-(t-butoxy-carbonylamino)ethyl)carbonyl)amino)propanoic acid methyl ester (2.0 g, 4 mmol) in CH2Cl2 (25 mL) was cooled to 0° C. and trifluoroacetic acid (25 mL) was added dropwise over 2 hours. At the end of the addition, the ice bath was removed and the mixture was stirred at ambient temperature. After 2 hours, the mixture was concentrated in vacuo. The residual yellow oil was taken up in ethyl acetate and washed with 1 N aqueous NaHCO3 solution. The organic layer was separated then dried over MgSO4, filtered, and concentrated in vacuo to afford 1.2 g (83% yield) of (2R,5S)-1-(4-fluorobenzyl)-2-(benzyloxy)methyl-5-methylpiperazine-3,6-dione, a compound of formula (R), as a clear oil; NMR (CDCl3) 7.4-7.2 (m, 7), 7.0 (dd, 2), 5.0 (1), 4.5-4.0 (m, 4), 3.9-3.5 (m, 4), 1.5 (d, 3) ppm, MS (LSIMS) 356.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([C:14](=[O:18])[CH2:15][NH:16][CH3:17])[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+].[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>CCOCC.O.CN(C)C=O>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[CH2:23]([N:16]([CH2:15][C:14]([N:12]1[C:11]2[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=2[S:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:18])[CH3:17])[CH:24]=[CH2:25]
Reactant: CNCC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Reactant: C=CCBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: C=CCN(C)CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2-(4-chlorophenyl)-4-(N-methylaminoacetyl)-3,4-dihydro-2H-1,4-benzothiazine (1.80 g), allyl bromide (0.52 ml), potassium carbonate (2.25 g) and dimethylformamide (20 ml) is stirred at room temperature for 3.5 hours. The reaction mixture is poured into water, and the mixture is extracted with ethyl acetate. After the solvent is distilled off, the residue is purified by silica gel column chromatography (solvent, chloroform: methanol=40 : 1). The caramel thus obtained is dissolved in ether and thereto is added 1.1 equivalent of oxalic acid. The resulting precipitate is washed with ether and dried to give 4-(N-allyl-N-methylaminoacetyl)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine oxalate as powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].[Br:18]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:18][C:7]1[C:2]([Cl:1])=[C:3]([C:16]#[N:17])[C:4](=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-n1ccc(Cl)c(C#N)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step D of Example 1 (4.00 g) in N,N-dimethylformamide (33 mL) was added N-bromosuccinimide (3.49 g) at 50° C. The reaction mixture was heated at 50° C. for 6 hr, cooled to room temperature, and diluted with water. The resulting solid was collected by filtration, and washed with acetonitrile. The solid was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.30 g).
Reaction SMILES: [OH-].[Na+].Br[CH2:4][C:5]1[C:6]([CH2:11]Br)=[CH:7][CH:8]=[CH:9][CH:10]=1.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:14][CH:15]=[CH2:16]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:15]([C:14]1([C:13]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:4]1)=[CH2:16]
Reactant: BrCc1ccccc1CBr
Reactant: C=CCC(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CC1(C(=O)OCC)Cc2ccccc2C1

Procedure:
Tetrabutylammonium bromide (0.31 g) and 48% NaOH solution (9 ml) were added to a flask. α,α'-dibromo-o-xylene (5.0 g) in toluene (15 ml) was then added to the flask. The mixture was stirred and ethyl 3-butenoate (2.16 g) in toluene (15 ml) was added dropwise at room temperature. After the addition the temperature was slowly raised to +60° C. The mixture was stirred at this temperature for 3.5 hours and then cooled. The toluene layer was separated, washed with water and evaporated at reduced pressure to give the desired product.