Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([NH:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]2=[O:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:20][C:21]1[S:25][N:24]=[C:23]([CH3:26])[CH:22]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:26][C:23]1[CH:22]=[C:21]([NH:20][C:2]2[CH:9]=[C:8]([NH:10][CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]3=[O:18])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[S:25][N:24]=1
Reactant: Cc1cc(N)sn1
Reactant: N#Cc1ccc(NC2CCCCNC2=O)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(NC3CCCCNC3=O)ccc2C#N)sn1
Reaction time: 18 h
Yield: 159.2 %

Procedure:
A mixture of 2-bromo-4-(2-oxoazepan-3-ylamino)benzonitrile (81 mg, 0.263 mmol), 5-amino-3-methylisothiazole hydrochloride (63 mg, 0.418 mmol), K2CO3 (120 mg, 0.869 mmol), BINAP (40 mg, 0.064 mmol) and Pd(OAc)2 (20 mg, 0.089 mmol) in dioxane (3 mL) was degassed with argon, then was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give 2-(3-methylisothiazol-5-ylamino)-4-(2-oxoazepan-3-ylamino)benzonitrile (143 mg)
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:15].[K+].[K+].S(=O)(=O)(O)O>>[CH3:11][C:10]1[C:9]2[NH:8][C:7](=[O:12])[C:6](=[O:13])[O:15][C:5]=2[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Cc1ccc2c(c1C)NC(=O)C2=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccc2oc(=O)c(=O)[nH]c2c1C
Reaction time: 0.25 h

Procedure:
35 parts of 6,7-dimethylisatin are introduced into a solution of 60 parts of potassium peroxydisulfate in 400 parts of 98% strength sulfuric acid at from 5° C. to 10° C. The mixture is then stirred for 10-20 minutes, after which it is poured onto ice. The product is filtered off and dried, giving 34 parts of 5,6-dimethyl-2,3-dioxo-1,4-benzoxazine, of melting point 278°-284° C. (with decomposition).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]1([CH3:49])[NH:29][C@H:28]2[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[N:22]([C:30]2[CH:38]=[C:37]3[C:33]([CH:34]=[CH:35][N:36]3[Si](C(C)C)(C(C)C)C(C)C)=[CH:32][CH:31]=2)[CH2:21]1>O1CCCC1>[NH:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([N:22]3[C@@H:23]4[C@@H:28]([CH2:27][CH2:26][CH2:25][CH2:24]4)[NH:29][C:20]([CH3:49])([CH3:19])[CH2:21]3)[CH:38]=2)[CH:34]=[CH:35]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(N3CC(C)(C)N[C@@H]4CCCC[C@@H]43)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CN(c2ccc3cc[nH]c3c2)[C@H]2CCCC[C@H]2N1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
Tetra-n-butyl ammonium fluoride (1 M in THF) (3.41 mL, 3.41 mol) was added to a tetrahydrofuran (15 mL) solution of (4aR,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H -indol-6-yl)decahydroquinoxaline (0.750 g, 1.71 mmol) with stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction mixture under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane) to obtain a white solid. The obtained solid was recrystallized from diisopropyl ether/hexane to obtain (4aR,8aS)-1-(1H-indol-6-yl)-3,3-dimethyldecahydroquinoxaline (305 mg, yield: 63%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].O1CCCC1.[N+:30]([O-:33])([OH:32])=[O:31]>C(#N)C>[CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].[N+:30]([O-:33])([O-:32])=[O:31]
Reactant: O=[N+]([O-])O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CC#N
Product: O=[N+]([O-])[O-]

Procedure:
The compound is prepared startaing from an Ampicillin solution (2 g, 5.72 rmoles) in a mixture formed by acetonitrile (30 ml) and tetrahydrofuran (20 ml), by adding a 65% nitric acid solution (0.450 ml) in acetonitrile (5 ml) and following the procedure reported in Example 5. Ampicillin nitrate as amorphous solid is obtained. Yield 55%.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:13])([O:11][CH3:12])[CH3:10])[CH2:3][CH:4]=O.[CH3:14][O:15][C:16](=[O:29])/[C:17](/[CH3:28])=[C:18](\P(OCC)(OCC)=O)/[CH3:19].[Na]>C1C=CC=CC=1.CO>[CH3:14][O:15][C:16](=[O:29])[C:17]([CH3:28])=[CH:18][CH:19]=[CH:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])([CH3:13])[CH3:10]
Reactant: CCOP(=O)(OCC)/C(C)=C(/C)C(=O)OC
Reactant: COC(C)(C)CCCC(C)CC=O
Agent: [Na]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(C)=CC=CCC(C)CCCC(C)(C)OC
Temperature: 60 °C
Reaction time: 5 h

Procedure:
29.5 g of 3,7-dimethyl-7-methoxy-octanal and 42 g of diethylphosphono-α-methyl-crotonic acid methyl ester are dissolved in 100 ml of absolute benzene. To this solution there is added dropwise 4.1 g of sodium dissolved in 50 ml of absolute methanol. The mixture is stirred for 5 hours at 60°C., poured on to ice-water and extracted with diethyl ether. The ethereal solution is washed with water, then with aqueous sodium bicarbonate solution and once again with water, dried with sodium sulphate, filtered and concentrated on a rotary evaporator. After chromatography on a 30-fold amount of Kieselgel, using hexane/diethyl ether (9:1 parts by volume) as the eluant, there is obtained 11-methoxy-2,7,11-trimethyl-2,4-dodecadienoic acid methyl ester; boiling point 100°C/0.002 mmHg.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1N.N([O-])=O.[Na+].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>Cl.O>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:25]=1
Reactant: Nc1ccccc1Sc1nc2ccccc2[nH]1
Reactant: COc1ccncc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccnc(-c2ccccc2Sc2nc3ccccc3[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 2-(1H-benzimidazol-2-yl thio)benzenamine (1.70 g) in dilute hydrochloric acid (11 ml) was added dropwise a solution of sodium nitrite (0.53 g) in water (5 ml), keeping the temperature below 0°. The reaction mixture was stirred at this temperature for 0.5 hours then added portionwise to a mixture of 4-methoxypyridine (42.40 g) and pyridine (0.57 g) stirring at 80° for 1 hour. The pyridines were distilled off, replaced with 880 ammonia which was in turn distilled off. The residue was treated with water, extracted into dichloromethane, washed, dried, evaporated and the residue was purified by flash column chromatography using ethyl acetate as eluant to give the sub-title product as a creamish foam, 0.20 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:42][NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH3:42][N:43]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:28])[F:27])[CH:19]=2)(=[O:16])=[O:17])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccccc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (458 mg, 1.00 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 2 h, then concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-methylaniline (108 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS), quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer was extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5 M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-phenylamide. MS m/z: 548.2 (M+H), 526.0 (M+H−MeOH).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([C:32]([O:34]CC)=[O:33])[O:30][CH3:31])=[CH:24][CH:23]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>>[C:32]([C@@H:29]([O:30][CH3:31])[CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[CH:27][CH:26]=1)([OH:34])=[O:33]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(-c3ccc(C(=O)OC)cc3)cc2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc(C(=O)O)cc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-4′-{3-[4-(2-Ethoxycarbonyl-2-methoxy-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylic acid methyl ester (Step A) by Standard Hydrolysis procedure C (NaOH). MS (ES) for C26H26O7 [M+NH4]+: 468, [M+Na]+: 473.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:32]([O:34][P:35](Cl)([O:37][CH2:38][CH3:39])=[O:36])[CH3:33].C(O)(=O)C>C1COCC1.O>[CH2:32]([O:34][P:35]([CH2:21][S:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)[CH2:17][CH2:16]1)(=[O:20])=[O:19])([O:37][CH2:38][CH3:39])=[O:36])[CH3:33]
Reactant: Cc1cc(N2CCN(S(C)(=O)=O)CC2)c2ccccc2n1
Reactant: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(CS(=O)(=O)N1CCN(c2cc(C)nc3ccccc23)CC1)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
2-Methyl-4-(4-methylsulfonylpiperazin-1-yl)quinoline (70 mg, 0.23 mmol) was placed in a Schlenk tube under an argon atmosphere, anhydrous THF (1.5 ml) was added and the solution cooled to −78° C. Lithium hexamethyldisilazid (50.6 mmol, 50.6 μl of a 1M solution in anhydrous THF) was added dropwise and the mixture stirred for one hour at −78° C. Diethylchlorophosphate (33.3 μl, 0.23 mmol) was added dropwise and stirring was continued for one hour. Acetic acid (100 μl) and water (1.5 ml) were added, the temperature raised slowly to room temperature and the mixture was extracted with diethylether (3×). The combined organic phases were washed with water and brine and evaporated to dryness under reduced pressure. 99 mg of an oily residue were obtained (0.22 mmol, 98%). MS (APCI) m/z=441.7 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6]/[C:5](=[C:7]2/[C:8](=[O:26])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([S:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19](O)=[O:20])[CH:11]=3)/[CH:4]=[C:3]1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CN.C1COCC1.[CH3:41][N:42](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:33][C:2]1([CH3:1])[O:6]/[C:5](=[C:7]2/[C:8](=[O:26])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([S:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([NH:42][CH3:41])=[O:20])[CH:11]=3)/[CH:4]=[C:3]1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(Sc4ccccc4C(=O)O)ccc32)C=C1N1CCOCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1Sc1ccc2c(c1)NC(=O)/C2=C1\C=C(N2CCOCC2)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoic acid in 5 mL of anhydrous DMF, were added 2M methylamine in THF solution (0.066 mL, 0.13 mmol), HBTU (49 mg, 0.13 mmol) and DIPEA (31 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 15 minutes and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product as a brown solid. Purification of the crude product by silica gel chromatography eluted with a gradient of 5-15% MeOH in CHCl3 afforded 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}-N-methylbenzamide as brown solid. Yield: 6 mg, 12%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:23]/[C:24]2[NH:25][CH:26]=[CH:27][C:28]=2[O:29][CH3:30])/[C:13](=[O:22])[NH:14]3)=[CH:6][CH:5]=1.[Cl-].[NH4+]>O.CO.[Zn]>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:23]/[C:24]2[NH:25][CH:26]=[CH:27][C:28]=2[O:29][CH3:30])/[C:13](=[O:22])[NH:14]3)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2c([N+](=O)[O-])ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2c(N)ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Yield: 46.7 %

Procedure:
Using Method L above, (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl) methylene]-5-nitro-2-oxo-1H-indol-4-yl]-benzoic acid methyl ester (85 mg, 0.22 mmol) (from Example 45 supra) was reduced with zinc (130 mg, 1.97 mmol) and ammonium chloride (25.8 mg, 0.48 mmol) in 10% water in methanol (10 mL) at reflux for 2 h to yield (Z)-4-[5-amino-2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl) methylene]-2-oxo-1H-indol-4-yl]-benzoic acid methyl ester (yield: 40 mg, 51%).
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=O)C(C)(C)C.C([O:45][CH2:46][C@@H:47]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])[C:48]1[C:49]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=2)=[C:50]2[C:55](=[CH:56][C:57]=1[CH3:58])[N:54]=[C:53]([NH:59][NH2:60])[CH:52]=[CH:51]2)(=O)C(C)(C)C>>[C:69]([O:68][C@@H:47]([C:48]1[C:49]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=2)=[C:50]2[C:55](=[CH:56][C:57]=1[CH3:58])[N:54]=[C:53]([NH:59][NH2:60])[CH:52]=[CH:51]2)[CH2:46][OH:45])([CH3:72])([CH3:70])[CH3:71]
Reactant: Cc1cc2nc(NN)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2nc(NN)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C

Procedure:
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-yl)ethanol was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol of Example 29 except using (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H27ClN3O2: 400.2. Found: 400.2.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[CH:32]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[O:30][CH:29]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].CO.NN>C1COCC1>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[CH:32]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[O:30][CH:29]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)co1
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)co1
Reaction time: 24 h

Procedure:
N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-3-furancarboxamide (200 mg, 0.38 mmol) was dissolved in THF (10 mL) and MeOH (10 mL) at RT and treated with hydrazine (0.19 mL, 3.8 mmole). After 24 h, the solution was concentrated and purified on silica using 8% MeOH in DCM (1% NH4OH) to give the title compound as a white solid. The free base was dissolved in DCM (5 mL) and treated with 4M HCl in dioxane (4 mL). After 5 min, the reaction solution was concentrated under vacuum to give the title compound (55 mg) as a di-HCl salt: LC-MS (ES) m/z=393 (M+H)+, 1H NMR (d6-DMSO) δ 8.78 (d, J=8.9 Hz, 1H), 8.38 (s, 1H), 8.16 (bs, 2H), 7.69 (d, J=7.6 Hz, 1H), 7.59 (m, 2H), 7.49 (s, 1H), 7.44 (m, 1H), 7.35 (s, 1H), 6.58 (s, 1H), 4.52 (m, 1H), 3.99 (s, 3H), 3.22 (m, 2H) and 3.07 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1)#[N:2].C(O)C.C(=O)([O-])O.[Na+]>O>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 82 °C
Yield: 91.9 %

Procedure:
A mixture containing ethyl p-cyanobenzoate (87.5 g, 0.5 mol), ethanol (192.5 g), and water (449.2 g) was placed in a 1 l-flask. The mixture was heated to 82° C., and sodium hydrogencarbonate was added thereto so as to adjust the pH of the mixture at 9.0-9.3. Seven hours after the reaction started, liquid chromatographic analysis revealed that the reaction mixture contained 67.6 g of p-cyanobenzoic acid (yield 92%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[C:38]([S:40][CH3:41])[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[C:21]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]([C:21]2[C:20]([NH:19][C:17](=[O:18])[C:16]3[CH:36]=[CH:37][C:38]([S:40][CH3:41])=[CH:39][C:15]=3[O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:27])=[N:30][CH:31]=1
Reactant: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
The 3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide (184 mg, 0.31 mmol) was dissolved in TFA (4 mL). After 5 minutes, the reaction was concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and extracted with saturated aqueous sodium carbonate (2×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the desired product as a white solid (139 mg, 0.28 mmol, 90%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]([CH3:34])[C:30](=[O:35])[CH:29]=2)=[CH:22][N:21]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]([CH3:34])[C:30](=[O:35])[CH:29]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:1]
Reactant: Cn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Solvent: CCO
Solvent: c1ccncc1
Product: CN(C)Cc1ccnc(CSCCNc2ncc(Cc3ccn(C)c(=O)c3)c(=O)[nH]2)c1
Yield: 56.5 %

Procedure:
2-[4-(Dimethylaminomethyl)pyrid-2-ylmethylthio]ethylamine (0.63 g) and 2-nitroamino-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (0.69 g) were refluxed in ethanol (12 ml) for 72 hours. As the reaction was not complete, the ethanol was replaced by pyridine (12 ml) and the solution refluxed for a further 6 hours. The reaction mixture was evaporated under reduced pressure to afford a residue which was washed with diethyl ether and recrystallised from isopropanol/ether to give 2-[2-[4-(dimethylaminomethyl)pyrid-2-ylmethylthio]ethylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (0.62 g), m.p. 137°-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9].CO.CCOC(C)=O.CCCCCCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: COc1cc(CC(=O)O)ccc1C
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CCO)ccc1C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
2-(3-methoxy-4-methylphenyl)acetic acid (1 g, 5.55 mmol) was dissolved in Tetrahydrofuran (27.7 ml). A solution of borane tetrahydrofuran complex (12.21 ml, 12.21 mmol) was added slowly under nitrogen. The reaction was stirred for about 18 h. Methanol was slowly to quench the reaction. The mixture was rotovapped. More methanol was added. The mixture was rotovapped. This was repeat two more times. The solution was passed through a short pad of silica gel eluting with 1:1 EtOAc/heptane and then rotovapped to give 2-(3-methoxy-4-methylphenyl)ethanol (0.800 g, 4.81 mmol, 87% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.07 (dd, 1H), 6.73 (dd, 1H), 6.69 (s, 1H), 3.86 (t, 2H), 3.30 (s, 3H), 2.84 (t, 2H), 2.14 (s, 3H), 1.41 (s, 1H)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])=[O:4].C(O)C#C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)(Cl)(Cl)Cl>[F:10][C:2]([F:1])([F:11])[S:3]([O:6][CH2:7][C:8]#[CH:9])(=[O:4])=[O:5]
Reactant: C=CCOS(=O)(=O)C(F)(F)F
Agent: C#CCO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: C#CCOS(=O)(=O)C(F)(F)F

Procedure:
2-Propyn-1-yl trifluoromethanesulfonate was prepared in carbon tetrachloride solution and used as a dried solution in Examples 45 through 48 in the same way that 2-propen-1-yl trifluoromethanesulfonate was prepared and was used in Examples 41 through 44 starting with 2-propyn-1-ol (propargyl alcohol) and trifluoromethanesulfonic anhydride.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](Cl)=[C:5]2[S:4][CH:3]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([NH:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:5]2[S:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cnc2c(C)csc2c1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2c(C)csc2c1NCc1ccccc1
Reaction time: 0.5 h

Procedure:
Ethyl 3-methyl-7-chlorothieno[3,2-b)pyridine-6-carboxylate (3.0 g, 0.0117 mol) and benzylamine (2.5 g, 0.0234 mol) were heated in an oil-bath with stirring for 30 minutes (oil-bath temperature to 220°). On cooling the residue was dissolved in chloroform, washed with dilute aqueous sodium hydroxide and the aqueous phase back-extracted with more chloroform. The combined chloroform extracts were washed with water, dried and evaporated to give an oil. This oil was purified by flash chromatography on silica (40-60 mesh) with dichloromethane as eluant to give an oil which crystallised on standing. Recrystallisation from methanol gives the title compound as pale yellow crystals, 3.0 g, m.p. 99°-100°.