Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[S:22]1C2CCCC(N)C=2C=C1>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[CH:15]=[CH:14][S:22][C:19]=3[CH2:18][CH2:17][CH2:16]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: NC1CCCc2sccc21
Product: CCc1cnc(CC)c(NC2CCCc3sccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 4,5,6,7-tetrahydro-1-benzothiophen-4-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.10 (d, J=5.2 Hz, 1H), 6.93 (d, J=5.2 Hz, 1H), 5.40 (m, 1H), 4.50 (bs, 1H), 2.83 (m, 2H), 2.66 (q, J=7.5 Hz, 2H), 2.56 (q, J=7.5 Hz, 2H), 2.10 (m, 1H), 1.96 (m, 3H), 1.29 (m, 6H); (MS/CI) calcd for C16H21N3S+H 287.4, found 287.9.
Reaction SMILES: [F:1][C:2]1([F:40])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]3[O:13][C:14]4[C:19]([C@@:20]5([CH2:24][S:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[N:21]5)[C:9]=3[CH:8]=2)=[CH:18][C:17]([C:33]2[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:16][CH:15]=4)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:40][C:2]1([F:1])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]3[O:13][C:14]4[C:19]([C@@:20]5([CH2:24][S:23][C:22]([NH2:25])=[N:21]5)[C:9]=3[CH:8]=2)=[CH:18][C:17]([C:33]2[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:16][CH:15]=4)[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(N3CCC(F)(F)C3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(N3CCC(F)(F)C3)cc12
Temperature: 25 °C
Reaction time: 68 h
Yield: 84.6 %

Procedure:
To a solution of (S)-tert-butyl 3-(3,3-difluoropyrrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazole]-2′-ylcarbamate (76.1 mg, 0.13 mmol) in DCM (1.34 mL) was added TFA (280 μL, 3.63 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 68 hours. The reaction was concentrated under reduced pressure and the resulting material was purified by “catch-and release” technique using a Varian Bond ELUT SCX column. The eluate was concentrated under reduced pressure to afford (S)-3-(3,3-difluoropyrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (52.14 mg, 0.11 mmol, 83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)ccc1CCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of 2-(4-chloro-2-nitro-phenyl)-ethanol (63.0 g, 0.31 mole) in methylene chloride (1 L) was added triphenylphosphine (81.9 g, 0.31 mole) and the mixture was cooled to 0° C. Carbon tetrabromide (103.6 g, 0.31 mole) in methylene chloride (100 mL) was added dropwise through an addition funnel. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, dichloromethane) to provide 78.0 g of the title compound as a light brown oil.
Reaction SMILES: [C:1]([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:4]/[CH:3]=[CH:2]/[C:1]([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C/C(=O)O[Si](C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)OC(=O)/C=C/CBr

Procedure:
To a single-neck reaction flask (250 mL) were added (E)-trimethylsilyl 2-butenoate (12.242 g, 77.481 mmol), NBS (16.550 g, 92.977 mmol), (PhCO2)2 (310 mg) and carbon tetrachloride (100 mL). The mixture was stirred under reflux for 3.5 hr. The resulting mixture was cooled in an ice-water bath. The insoluble substance was filtered. The residue was rotatory-evaporated and concentrated until no liquid dropped. The concentrate was distilled under reduced pressure to collect the fraction under 9 mmHg at the temperature of 100° C.-102° C. to give the target compound as a colorless transparent liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)=O.NC1C=CC(C)=CC=1NC(C1CN(C(OC(C)(C)C)=O)C1)=O>CC(O)=O>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:10]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)=[N:1][C:2]=2[CH:7]=1
Reactant: Cc1ccc(NC(=O)C2CN(C(=O)OC(C)(C)C)C2)c(N)c1
Agent: Cc1ccc(N)c(NC(=O)C2CN(C(=O)OC(C)(C)C)C2)c1
Solvent: CC(=O)O
Product: Cc1ccc2[nH]c(C3CN(C(=O)OC(C)(C)C)C3)nc2c1
Temperature: 100 °C

Procedure:
A solution of tert-butyl 3-(2-amino-4-methylphenylcarbamoyl)azetidine-1-carboxylate and tert-butyl 3-(2-amino-5-methylphenylcarbamoyl)azetidine-1-carboxylate (prepared in the previous step) in AcOH (40 mL) was heated to 100° C. for 1.5 h and concentrated. The product tert-butyl 3-(5-methyl-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:11](=[O:12])[CH:10]2[CH2:13][CH2:14][CH2:15][C:9]2=[N:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.Cl.C(O)C.[BH4-].[Li+].[Na+].[BH4-].O>ClCCl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:11](=[O:12])[CH:10]2[CH2:13][CH2:14][CH2:15][CH:9]2[NH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2
Reactant: O=C1C2CCCC2=Nc2ccccc2N1Cc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: O=C1C2CCCC2Nc2ccccc2N1Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.9 %

Procedure:
To a solution of 9-(2,4-dichlorobenzyl)-2,3,9,10a-tetrahydrobenzo [b]cyclopenta[e][1,4]diazepin-10(1H)-one (0.9 g, 2.5 mmol) in dichloromethane (3 mL) was added 2.5N HCl-ethanol solution (1.5 mL), and the mixture was immediately concentrated under reduced pressure. The concentrate was dissolved in methanol (10 mL), to which was added sodium lithium borohydride (250 mg, 6.6 mmol). The mixture was stirred for 20 minutes at room temperature. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate three times. The organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, which was subjected to filtration. The filtrate was concentrated under reduced pressure, and the concentrate was purified by silica-gel column chromatography (hexane-ethyl acetate 6:1) to give 740 mg (yield 82%) of the titled compound. Amorphous.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1F
Reactant: CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ccccc2C=O)cc1
Temperature: 100 °C

Procedure:
2-Fluorobenzaldehyde (31.6 mL, 300 mmol) and 4-(methylmercapto)phenol (46.27 g, 330 mmol) were dissolved in DMF (500 mL) and potassium carbonate (62.2 g, 450 mmol) was then added. The mixture was heated at 100° C. for 12 h under a nitrogen atmosphere. After cooling to room temperature the mixture was evaporated to dryness, co-evaporated with toluene and then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried (MgSO4) and evaporated to a brown oil of the desired aldehyde material (84.4 g) which was contaminated with ca 15% of starting phenol, but sufficiently pure to use directly in the next stage; δH(CDCI3, 400 MHz) 2.47 (3 H, s), 6.87 (1 H, d), 6.99 (2 H, m), 7.17 (1 H, m), 7.29 (2 H, m), 7.49 (1 H, m), 7.92 (1 H, d), 10.49 (1 H, s). If required the crude mixture can be purified by flash chromatography [SiO2; ethyl acetate/ hexanes (2→10%)] to obtain a pure sample of the desired aldehyde compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: COc1ccc2c(c1C#CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1/C=C\CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperidine-1-carboxylate (0.0775 g, 0.201 mmol) synthesized in Example B58, Step 2 in ethanol (5 mL) was added with 5% palladium/carbon (wetted with 50% water, 0.0800 g), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, the resulting filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl]piperidine-1-carboxylate (0.0671 g, 86%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:15]2[C:26]2[CH:31]=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][NH2:37]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:15]2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:37][CH3:36])[N:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)ccn2C2CCN(Cc3ccccc3)CC2)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nccc(-c2c(-c3ccc(F)cc3)ccn2C2CCN(Cc3ccccc3)CC2)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A mixture of 1.19 g (2.43 mmol) of 1-(1-benzylpiperidin-4-yl)-3-(4-fluorophenyl)-2-(2-methanesulfonylpyrimidin-4-yl)-1H-pyrrole [prepared as described in Step 42(ii) above] and 13 ml of a 2M solution of methylamine in tetrahydrofuran was stirred at 100° C. for 30 minutes in a sealed tube. At the end of this time, the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 1:2 by volume mixture of hexane and ethyl acetate as the eluant to give 260 mg (yield 24%) of the title compound as a yellow amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:28])=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20]([OH:22])=O)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[O:29]([NH2:31])[CH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:28])=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20]([NH:31][O:29][CH3:30])=[O:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Reactant: CON
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NOC)c1=O

Procedure:
This compound was prepared from [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-[(methylamino)carbonyl]-2-oxo-1,5-naphthyridine-1(2H)-yl]acetic acid and methoxylamine employing methods similar to those described in example 558. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.39 (1H, br s), 9.96 (1H, br s), 8.55 (1H, s), 7.88 (1H, s), 7.36-7.31 (2H, m), 7.14-7.09 (2H, m), 4.80 (2H, s), 4.11 (2H, s), 3.52 (3H, s), 2.88 (3H, d, J=4.8 Hz); HRMS calcd for C20H19FN4O5+H+: 415.1412. Found 415.1416.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][CH:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[CH:6]2[CH2:5]1.[CH2:18]([C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1)[CH3:19]>CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:22][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([OH:21])[CH2:18][CH3:19])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: CCC1(c2ccncc2)CO1
Reactant: Cc1ccc2c(c1)C1CN(C)CCC1N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(O)(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A flask was charged with sodium hydride (0.640 g, 50-60%) in dry DMF (10 mL) at 0° C. and to this was added 2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (0.8 g). The mixture was stirred at RT for 30 min. and then 4-(2-ethyloxiran-2-yl)pyridine (0.834 g) dissolved in DMF (2 mL) was added, stirred at RT for 12 h. The reaction mixture was diluted with ice-water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated. The crude product was triturated with diethyl ether to obtain the desired compound. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.45 (d, 2H), 7.42 (d, 2H), 7.30 (d, 1H), 7.10 (s, 1H), 6.82 (d, 1H), 4.30 (d, 1H), 4.18 (d, 1H), 3.60 (s, 2H), 3.50 (m, 2H), 3.38 (m, 1H), 3.0 (m, 2H), 2.90 (s, 3H), 3.32 (s, 3H), 2.10 (m, 1H), 0.6 (t, 3H).
Reaction SMILES: C1(C)C=CC(=[C:7]2[CH:12]3[C:13]([CH3:15])([CH3:14])[C:9]([CH3:16])([CH2:10][CH2:11]3)[C:8]2=[O:17])CC=1.[OH:19][S:20]([OH:23])(=O)=[O:21].O=S(=O)=O.[Cl-].[Na+:29]>>[CH3:16][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[C:7]2[CH:12]3[C:13]([CH3:15])([CH3:14])[C:9]([CH3:16])([CH2:10][CH2:11]3)[C:8]2=[O:17])=[CH:7][C:8]=1[S:20]([O-:23])(=[O:21])=[O:19].[Na+:29]
Reactant: CC1=CCC(=C2C(=O)C3(C)CCC2C3(C)C)C=C1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc(C=C2C(=O)C3(C)CCC2C3(C)C)cc1S(=O)(=O)[O-]

Procedure:
25.4 g of 3-p-tolylidene camphor are added to 64 ml of oleum containing 10% SO3, with cooling so as to keep the temperature of the reaction mixture around 35° C. The resulting mixture is then poured into 150 ml of a saturated sodium chloride solution, the mixture being cooled to below 25° C. A precipitate is obtained which is filtered and then washed with a saturated sodium chloride solution. The wet product is made into paste in 70 ml of water. It is then filtered and recrystallized in an 80:20 water-acetone mixture. Thus, 29.3 g of a white powder, melting at 240° C. are obtained.
Reaction SMILES: COC(/C=C/[C:7]1[CH:12]=[C:11](O)[C:10]2[O:14][CH:15](C3C=CC(O)=C(O)C=3)[CH:16](C(OC)=O)[C:9]=2[CH:8]=1)=O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[O:14]1[C:10]2[CH:11]=[CH:12][CH:7]=[CH:8][C:9]=2[CH:16]=[CH:15]1
Reactant: COC(=O)/C=C/c1cc(O)c2c(c1)C(C(=O)OC)C(c1ccc(O)c(O)c1)O2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: c1ccc2occc2c1
Yield: 93 %

Procedure:
A mixture of dihydrobezofuran a (Davies, H. M. L.; Grazini, M. V. A.; Aouad, E. Org. Lett. 2001, 3, 1475) (160 mg, 0.9 mmol) DDQ (300 mg) and CH2Cl2 (11 mL) was maintained at room temp. for 2 days. The solution was diluted with 50% ethyl acetate-hexanes and washed with 0.5 N NaOH (3×10 mL), brine (1×10 mL), dried (Na2SO4), filtered, and concentrated to afford 150 mg (93%) of bezofuran b.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[C:10]1([NH:16][C:17]#[N:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na]>O1CCOCC1.O>[C:17]([N:16]([C:2]1[N:4]=[C:5]([N:16]([C:17]#[N:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:8]([N:16]([C:17]#[N:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:1]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:18]
Reactant: N#CNc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: N#CN(c1ccccc1)c1nc(N(C#N)c2ccccc2)nc(N(C#N)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 9.20g (0.05 mole) of cyanuric chloride in 100 ml of dioxane was added to 100 ml of ice water. To this mixture at room temperature was added dropwise a solution of 0.15 mole of sodium phenylcyanamide in 70 ml of water over a 30 minute period. After stirring for 3 hours at room temperature, the reaction mixture was refluxed for 16 hours. After cooling to room temperature the reaction mixture was filtered. The residue was washed with water and dried to give 17.2g (80%) of of TNCT, m.p. 209°-215°. Recrystallization from toluene gave 10.8g with an m.p. of 215°-218°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5](=[O:12])[N:6]([CH2:8][O:9][CH2:10][CH3:11])[CH:7]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCOCC1>[C:14]([O:13][C:3]1[C:2]([Cl:1])=[CH:7][N:6]([CH2:8][O:9][CH2:10][CH3:11])[C:5](=[O:12])[CH:4]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOCn1cc(Cl)c(O)cc1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOCn1cc(Cl)c(OC(=O)c2ccccc2)cc1=O
Yield: 93 %

Procedure:
The general procedure of Example 49 was followed using 200 mg of 5-chloro-1-ethoxymethyl-4-hydroxy-2-pyridone, 0.14 ml of benzoyl chloride, 0.68 ml of triethylamine and 20 ml of dioxane, thereby producing 280 mg of the title compound in a yield of 93%.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[CH:14][C:13]=1[NH:21][C:22]1[C:31]2[C:26](=[CH:27][C:28](F)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:35]#[N:36].C(=O)(O)[O-].[Na+]>CS(C)=O>[CH2:3]([O:10][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:21][C:13]3[CH:14]=[C:15]([O:19][CH3:20])[C:16]([Cl:18])=[CH:17][C:12]=3[Cl:11])=[C:23]([C:35]#[N:36])[CH:24]=[N:25]2)=[CH:30][C:29]=1[O:32][CH3:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: OCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(Nc2c(C#N)cnc3cc(OCc4ccccc4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73.1 %

Procedure:
To a mixture of sodium hydride (122 mg, 3.04 mmol) in 6 mL of dimethylsulfoxide is added benzyl alcohol (91 mg, 0.84 mmol). The solution is stirred at room temperature for 40 minutes. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (300 mg, 0.76 mmol) is added and the reaction mixture is heated at 100° C. for 3 hours then cooled to room temperature and allowed to stir overnight. The reaction mixture is poured into saturated sodium bicarbonate and the solids are collected by filtration. Purification by flash column chromatography eluting with 10% ethyl acetate in dichloromethane provides 267 mg of 7-benzyloxy-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile, mp 198-200° C.
Reaction SMILES: F[C:2]1[C:3]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[CH3:19][NH2:20].Cl>>[CH3:19][NH:20][C:2]1[C:3]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6]
Reactant: CS(=O)(=O)c1c(C(=O)O)ccc(C(F)(F)F)c1F
Reactant: CN
Agent: Cl
Product: CNc1c(C(F)(F)F)ccc(C(=O)O)c1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.40 g (8.4 mmol) of 3-fluoro-2-methylsulfonyl-4-trifluoromethylbenzoic acid were treated with 12.1 ml (168 mmol; 40 percent strength) of aqueous methylamine solution and the mixture was stirred for 4 h at RT. For work-up, the contents were poured into 6 N HCl, the mixture was subsequently cooled in an ice-bath. The precipitate was filtered off with suction. This gave 2.50 g of product in 95% purity.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:17]1([CH2:20][C:21]([NH2:29])([CH3:28])[C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][C:21]([NH:29][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])([CH3:28])[C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH2:19][CH2:18]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(Cl)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 66e) as starting materials and isolated (29 mg, 51%) as colorless oil; MS (ESI, m/z): 419.5 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:5])[CH3:2].[C:20]([O-])([O-])=O.[Cs+].[Cs+].IC>CC(C)=O>[CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[C@H]1[C@@H](c2ccc(O)cc2)CC(=O)N1C
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)[C@H]1[C@@H](c2ccc(OC)cc2)CC(=O)N1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
To a solution of (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-hydroxyphenyl)pyrrolidin-2-one (prepared according to the procedure described for Intermediate W, 0.74 g, 2.81 mmol) in acetone (10 mL) was added Cs2CO3 (2.03 g, 5.62 mmol), followed by iodomethane (0.19 mL, 3.1 mmol). The reaction was stirred at room temperature for 72 h and filtered. The filtrate was concentrated under reduced pressure. The resulting oil was purified by flash chromatography (EtOAc) to yield (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-methoxy-phenyl)pyrrolidin-2-one (0.72 g, 93%) as a white solid: 1H NMR (DMSO-d6) δ 0.73 (t, J=6.0 Hz, 3H), 2.44-2.71 (m, 5H), 3.56-3.78 (m, 5H), 3.88 (q, J=8.8 Hz, 1H), 4.42 (d, J=8.8 Hz, 1H), 6.82-6.87 (m, 2H), 7.11-7.16 (m, 2H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=1)([CH3:7])[CH3:6])C.[BH4-].[Na+]>CO>[Br:14][C:12]1[CH:13]=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])[CH:9]=[N:10][CH:11]=1
Reactant: CCOC(=O)C(C)(C)c1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CO)c1cncc(Br)c1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
To a solution of 2-(5-bromo-pyridin-3-yl)-2-methyl-propionic acid ethyl ester (2.4 g, 0.009 mol) in MeOH (30 mL) is added sodium borohydride (1.7 g, 0.044 mol). The resulting mixture is heated to reflux for 5 h. The reaction is cooled to room temperature and concentrated then is washed with water and extracted with DCM. The combined organic layers are dried (Na2SO4), concentrated and purified by silica gel column to obtain 2-(5-bromo-pyridin-3-yl)-2-methyl-propan-1-ol (661 mg).