Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:25][C:26]1([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:29][NH:28][CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:28]3[CH2:29][C:26]([CH2:30][N:31]([CH3:33])[CH3:32])([F:25])[CH2:27]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CN(C)CC1(F)CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 1.8 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.50 g, 1.0 eq.) was dissolved in DCM (10 mL). The reaction mixture was cooled to −60° C., at which temperature 1-(3-fluoroazetidin-3-yl)-N,N-dimethylmethanamine (0.22 g, 1.2 eq) and T3P (50% in EtOAc) (1.08 g, 1.2 eq.) were added, followed by DIPEA (0.36 g, 2 eq.). The clear reaction mixture was stirred at −60° C. for 45 min. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography to give 12 mg of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3-((dimethylamino)methyl)-3-fluoroazetidin-1-yl)prop-2-en-1-one (3% yield). 1H NMR (400 MHz, CDCl3) δ=9.75 (s, 1H), 8.62 (s, 2H), 7.94 (s, 1H), 7.24-7.21 (d, J=10.8 Hz, 1H), 5.69-5.66 (d, J=10.8 Hz, 1H), 4.37-4.25 (m, 2H), 4.22-4.15 (m, 2H), 2.82-2.76 (d, 2H), 2.35 (s, 2.35, 1H); LCMS for C19H19F7N5O [M+H]+ 466.4 found 466.3 at retention time 2.263 min
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5](=[CH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:4][CH2:3]1.ClC(OCC)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].Cl>O1CCCC1.C(N(CC)CC)C>[CH2:21]([N:23]([CH2:24][CH3:25])[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]=[C:5]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]1)[CH3:22]
Reactant: O=C(O)CCCC=C1CCC(=O)CC1
Reactant: CCNCC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CCCC=C1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 21 ml of anhydrous tetrahydrofuran were dissolved 1.50 g of 5-(4-oxocyclohexylidene)-valeric acid and 1.17 ml of triethylamine. Then, 4.50 ml of a solution of 0.80 ml of ethyl chloroformate in anhydrous tetrahydrofuran was dropwise added at −20° C., and the resulting mixture was stirred at the same temperature as above for one hour. Then, 4.50 ml of a solution of anhydrous tetrahydrofuran containing 2.00 ml of diethylamine was dropwise added at the same temperature, and the resulting mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturate aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=1:1] gave 1.30 g of N,N-diethyl-5-(4-oxocyclohexylidene)-valeramide as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:10]([NH2:13])[NH:11][N:12]=1.[C:21](OCC)(=[O:26])[CH2:22][C:23]([CH3:25])=O.C(OCC)C>C(O)(=O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:12][N:11]3[C:21]([OH:26])=[CH:22][C:23]([CH3:25])=[N:13][C:10]=23)=[CH:19][CH:18]=1
Reactant: Nc1[nH]nc(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc(O)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 100 °C

Procedure:
To a mixture of 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-1b; 3.00 g, 9.86 mmol) in acetic acid (12 ml) was added ethyl acetoacetate (1.63 ml, 12.8 mmol). The reaction was heated at 100° C. for 16 hours. After cooling to room temperature, the precipitated solid was isolated by vacuum filtration and then repulped from diethyl ether to afford I-3A-4a (1.1 g, 30%) as a colorless solid: +ESI MS (M+1) 370.0; 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.45–7.33 (m, 6H), 7.13 (d, J=8.7 Hz, 2H), 5.70 (s, 1H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1cc(Cl)cc(Cl)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 76.5 %

Procedure:
3,5-dichloroaniline (132 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3,5-dichlorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (75 mg, 75%) as a white solid. Mass Spectrum: M+H+ 490. NMR Spectrum (DMSOd6): 1.52 (d, 3H), 2.75 (bs, 3H), 2.95 (bs, 3H), 3.51-3.63 (m, 4H), 3.70-3.78 (m, 4H), 5.01-5.09 (m, 1H), 5.61 (s, 1H), 6.50 (s, 2H), 6.61 (s, 1H), 6.91 (d, 1H), 7.54 (d, 1H), 7.81 (d, 1H)
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH:28]=O)=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl.[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])[CH3:32]>CC(O)=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][N:39]5[CH2:40][CH2:41][CH:36]([C:34]([O:33][CH2:31][CH3:32])=[O:35])[CH2:37][CH2:38]5)=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)Oc1ncc(-c2nc(-c3ccc4c(C=O)c[nH]c4c3)no2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2c[nH]c3cc(-c4noc(-c5cnc(OC(C)C)c(Cl)c5)n4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Sodium hydroxide (5.5 mL, 0.5 M in EtOH) was added to a mixture of 6-[5-(5-chloro-6-isopropoxy-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-1H-indole-3-carbaldehyde (D102) (200 mg) and piperidine-4-carboxylic acid ethyl ester hydrochloride (507 mg). The reaction mixture was stirred at room temperature for 10 mins, and AcOH (0.5 ml) was added. After the solvent was evaporated, the residue was dissolved in DCM (40 mL). NaBH(OAc)3 (554 mg) was then added in one portion. After stirred overnight, the reaction was quenched with saturated aqueous sodium bicarbonate solution, and extracted with DCM for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by Mass Directed AutoPrep to afford ethyl 1-{[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-4-piperidinecarboxylate (D103) (140 mg) as a white solid. MS (ES): C27H30ClN5O4 requires 523; found 524.2.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:11](Cl)(=[O:16])/[C:12](=[CH:14]/[CH3:15])/[CH3:13]>Cl>[CH3:13][CH:12]1[CH:14]([CH3:15])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:11]1=[O:16]
Reactant: C/C=C(\C)C(=O)Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC1C(=O)c2ccccc2C1C
Temperature: 7 °C
Yield: 91.8 %

Procedure:
Under an argon atmosphere benzene (335 ml, 3.74 mol) and aluminum trichloride (90.78 g, 0.68 mol) were introduced into a 1 liter three necked round bottomed flask fitted with a magnetic stirring apparatus, an addition funnel and a reflux condenser. The stirred orange mixture was cooled to 7° C. and tigloyl chloride (33) (40 g, 0.34 mol) was added dropwise via an addition funnel. After completion of the addition, the mixture was allowed to come to room temperature and then refluxed overnight. Then the reaction mixture was allowed to come to room temperature and poured onto mixture of ice (300 g) and conc. HCl (50 ml). The organic layer was separated and washed with a saturated solution of sodium bicarbonate (3×100 ml), then dried over magnesium sulfate and filtered. The excess benzene was removed under reduced pressure to afford (34) (50.02 g, 92%) as a yellow liquid. The 1H NMR spectrum was identical with the literature (T. E. Ready, J. C. W. Chien, M. D. Rausch, J. Org. Chem. 1999 583, 11-27; J. Sarrazin, A. Tallec, Tetrahedron Letters, 1977, 18, 1579-1582; M. Hiscock, G. B. Porter, J. Chem. Soc. (B), 1971, 1631-1634).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:38])[NH:21][C:9]4[CH:10]=[C:11]([C:19]#[N:20])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[O:36][N:35]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C#N)NC(=O)CC(c1cccc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from [4-cyano-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example M93) (0.36 g, 0.68 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (94 mg, 34%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)[CH2:2]1.[NH2:20][CH:21]1[CH2:26][CH2:25][C:24]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][C@H:33]([OH:36])[C@@H:32]([CH3:37])[CH2:31]2)([OH:27])[CH2:23][CH2:22]1>>[OH:27][C:24]1([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][C@H:33]([OH:36])[C@@H:32]([CH3:37])[CH2:31]2)[CH2:25][CH2:26][CH:21]([NH:20][C:17]([C:11]2[NH:12][C:13]3[C:9]([CH:10]=2)=[C:8]([O:7][CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[CH:16]=[CH:15][CH:14]=3)=[O:19])[CH2:22][CH2:23]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCC3CCOC3)cccc2[nH]1
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCC5CCOC5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(tetrahydro-furan-3-ylmethoxy)-1H-indole-2-carboxylic acid 16b and amine 14.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([OH:16])[CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O>ClCCl>[C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([O:16][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nccc1[C@H]1CC[C@H](O)C[C@@H]1OC(=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cn1nccc1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1OC(=O)c1ccccc1
Yield: 81.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 162e by using the (1S*,2R*,5S*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate (290 mg, 0.966 mmol) prepared in Example 163d, 2,6-lutidine (0.136 mL, 1.17 mmol), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.269 mL, 1.17 mmol) and dichloromethane (5.0 mL), to yield the title compound (327 mg, 82%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:16])=[O:15])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Cl[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1>C1COCC1>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([C:8]2[C:9]([NH:13][S:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:15])=[O:16])=[N:10][CH:11]=[N:12][C:7]=2[O:6][CH2:5][CH2:4][O:3][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCOc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 17 h
Yield: 88.8 %

Procedure:
To sodium hydride (27 mg, 60% in mineral oil) was added THF (15 ml) followed by 2-phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (80 mg, Referential Example 1). The mixture was stirred for 1 h at rt before 2-chloro-5-trifluoromethyl-pyridine (86 mg) was added. Stirring was continued for 17 h at 80° C. The solvent was evaporated, the residue was dissolved in water (20 ml), acidified with citric acid. The suspension was treated with hexane (15 ml). The solid material was collected, washed with hexane:EA 1:1 (20 ml) and dried to yield 2-phenyl-ethanesulfonic acid {5-p-tolyl-6-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide (96 mg) as beige powder. LC-MS: tR=5.86 min, [M+1]+=559.20, [M−1]−=557.37.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]3[O:43][CH2:42][C:41](=[O:44])[NH:40][C:39]=3[CH:45]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[CH:37][C:38]5[O:43][CH2:42][C:41](=[O:44])[NH:40][C:39]=5[CH:45]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)CO3)OC1(C)C
Product: CC1Cc2ccc(-c3ccc4c(c3)NC(=O)CO4)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 129, Step 4 starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.0209 g, 0.0500 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one. LCMS (M+H)+: m/z=486.2.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].O.[NH2:23][NH2:24]>CCO>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:23][NH2:24])=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(C#N)cc2)cc1
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
To a suspension of methyl 4-[(4-cyanobenzoyl)amino]benzoate (680 mg, 2.43 mmol) in EtOH (8 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (1×2 mL) and water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 432 mg of the title compound (64%) as a pale yellow solid in 94.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1CCN2C(=NCCC2)CC1.[CH2:30]([O:37][C:38]([N:40]1[C@@H:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:43]([CH:49]=O)[O:42][C:41]1([CH3:52])[CH3:51])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C1COCC1>[CH2:30]([O:37][C:38]([N:40]1[C@@H:44]([CH2:45][CH:46]([CH3:47])[CH3:48])[C@H:43]([CH:49]=[C:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:42][C:41]1([CH3:51])[CH3:52])=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)C[C@H]1[C@H](C=O)OC(C)(C)N1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CC
Yield: 88.1 %

Procedure:
71.6 mg of lithium chloride was suspended in 5 ml of dry THF under an argon atmosphere, and 426 mg of ethyl 2-diethylphosphonobutanoate dissolved in 0.6 ml of dry THF was added thereto under stirring. The mixture was stirred at room temperature for 5 minutes, and then 323 mg of 1,8-diazabicyclo[5,4,0]-7-undecene (hereinafter referred to simply as DBU) was added thereto in the form of a 50% dry THF solution, and the mixture was stirred at room temperature for 10 minutes. Then, 450 mg of (4S,5R)-3-benzyloxycarbonyl-2,2-dimethyl-5-formyl-4-isobutyloxazolidine dissolved in 1.0 ml of dry THF was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was cooled to 0° C. and neutralized with 1N hydrochloric acid. Then, the solution was extracted three times with ethyl acetate. The organic layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 518 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-ethyl-2-propenoate as colorless oily substance.
Reaction SMILES: [IH:1].CS[C:4](=[NH:19])[NH:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC(O)(C)C>[IH:1].[C:7]1([CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:5][C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[NH:19])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCNCC1
Reactant: CSC(=N)NC(c1ccccc1)c1ccccc1
Agent: I
Solvent: CC(C)(C)O
Product: N=C(NC(c1ccccc1)c1ccccc1)N1CCCCC1

Procedure:
To a suspension of 9.61 g (0.025 mole) of methyl-N-(diphenylmethyl)-carbamimidothioate hydroiodide in 20 ml of t-BuOH is added 4.26 g (0.05 mole) of piperidine. The mixture is heated under reflux over night. The resulting crystals after cooling in ice, are filtered; mp 200°-213° C. One recrystallization from methanol-t-BuOH yields the pure product, N-(diphenylmethyl)-1-piperidinecarboximidamide monohydroiodide as a white crystalline solid; mp 207°-210° C.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:14])([CH3:13])[C:8]1[CH:9]=[N:10][NH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17][O:18][C:19](=[O:22])[CH2:20]Br>CN(C=O)C>[CH3:17][O:18][C:19](=[O:22])[CH2:20][N:10]1[CH:9]=[C:8]([C:7]([CH3:14])([CH3:13])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=[N:11]1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C(C)(C)O[SiH2]C(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-1H-pyrazole (348 mg) was dissolved in DMF (12 mL) and cooled to 0° C. To this solution was added NaH (60% in mineral oil, 111 mg). The mixture was stirred at 0° C. for 30 minutes and then methylbromoacetate (0.23 mL) was added dropwise. The mixture was stirred at r.t. overnight. The reaction mixture was poured into ice/water and extracted with chloroform. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=100:0 to 0:100) to give the title compound as a yellow oil (484 mg, 98%). MS (m/e)=285.0 [MH+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:13])=[CH:11][N:12]=1)[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[CH:14](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([O:13][CH3:14])=[CH:11][N:12]=1)[C:8]#[N:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(C#N)c(O)cn1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COc1cnc(C(C)(C)C)cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
To a solution of 2-tert-butyl-5-hydroxy-isonicotinonitrile (10.0 g, 73.5 mmol) in acetonitrile/methanol (9:1, 20 mL) was added N,N-diisopropylethylamine (1.48 mL, 8.52 mmol) followed by (trimethylsilyl)diazomethane (2.0M in hexane, 4.30 mL, 8.52 mmol). The red solution was stirred for 18 h at room temperature and then concentrated in vacuo. The residue was dissolved in methylene chloride, washed with saturated aqueous NaHCO3 dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-tert-butyl-5-methoxy-isonicotinonitrile (1.10 g, 99%) as a pale yellow oil which was utilized without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1
Reactant: COc1ccc(NC(C)=O)c(C)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(C)c(NC(C)=O)cc1[N+](=O)[O-]
Yield: 53 %

Procedure:
34 g (0.19 mol) of N-(4-methoxy-2-methylphenyl)acetamide were added in small portions to a mixture of 40 ml of glacial acetic acid and 70 ml of fuming nitric acid at −10 to −15° C. These portions were such that the temperature did not rise above −10° C. The reaction mixture was then poured onto ice. The resulting precipitate was filtered off with suction and washed with water, ethanol and diethyl ether. 22.5 g (53%) of the desired product were obtained.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.[C:12]([C:15]1[S:19][CH:18]=[N:17][C:16]=1[CH3:20])(=[O:14])[CH3:13].O>C(OCC)C>[O:4]1[CH:5]=[CH:6][C:2]([C:12]([C:15]2[S:19][CH:18]=[N:17][C:16]=2[CH3:20])([OH:14])[CH3:13])=[CH:3]1
Reactant: CC(=O)c1scnc1C
Reactant: Brc1ccoc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Cc1ncsc1C(C)(O)c1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromofuran (6.8 g) in diethylether (15 ml) was added dropwise to n-butyllithium (2.5M solution in hexane, 18.4 ml) in diethylether (20 ml) at -70° C. under a nitrogen atmosphere. After 1 hour, 5-acetyl-4-methylthiazole (5 g) in diethylether (15 ml) was added dropwise. After a further 3 hours at -70° C., the mixture was allowed to warm to room temperature and was then left overnight. The mixture was poured into water and extracted with diethylether. The product thus obtained was crystallised from diethylether, m.p. 102°-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([NH2:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([NH:30][C:13]([C:11]1[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:9][CH:10]=1)=[O:15])=[CH:25][CH:24]=2)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)o1
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccc(-c4cccc(Cl)c4)o3)ccc2[nH]1

Procedure:
5-(3-Chloro-phenyl)-furan-2-carboxylic acid (65) (54 mg, 0.24 mmol) was coupled to ethyl ester (58) (50 mg, 0.24 mmol) using Method C. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.