Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[F:6][CH:7]([F:22])[C:8](=[N+:19](C)C)/[C:9](/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10]\[N:11](C)[CH3:12].CNN>C(#N)C>[F:6][CH:7]([F:22])[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][N:11]([CH3:12])[N:19]=1
Reactant: CCOC(=O)/C(=C/N(C)C)C(C(F)F)=[N+](C)C
Agent: CNN
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.0 g (30 mmol) of N-[(2E)-1-(difluoromethyl)-3-(dimethylamino)-2-(ethoxycarbonyl)prop-2-en-1-ylidene]-N-methylmethanaminium tetrafluoroborate were dissolved in 50 ml of acetonitrile and admixed with 2.3 g of methylhydrazine. After stirring at RT for 2 h, the acetonitrile was removed completely under reduced pressure. Distillation under reduced pressure or crystallization from n-hexane afforded 5.3 g (86% of theory) of the product having an m.p. of 63-65° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][OH:11])=[C:6]([Cl:12])[C:5]([F:13])=[CH:4][CH:3]=1.[CH:14](O)=O>>[Cl:12][C:6]1[C:7]2[N:8]([CH2:9][CH2:10][OH:11])[CH:14]=[N:1][C:2]=2[CH:3]=[CH:4][C:5]=1[F:13]
Reactant: O=CO
Reactant: Nc1ccc(F)c(Cl)c1NCCO
Product: OCCn1cnc2ccc(F)c(Cl)c21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-[(6-Amino-2-chloro-3-fluorophenyl)amino]ethanol (2.07 g, 10.2 mmol) is dissolved in formic acid (50.0 mL), and the resulting solution is heated to 100° C. for 1 hour. The solution is cooled to room temperature and then evaporated to dryness. The residue is suspended in NH3 (50.0 mL, 2N in EtOH) and stirred for 1 hour. The solution is concentrated to dryness, and the residue is suspended in EtOAc (50.0 mL). The organic phase is washed with 2N NaOH (50.0 mL), and the resulting aqueous phase is extracted 4 times with EtOAc (4×50.0 mL). The combined organic phases are dried with MgSO4, filtered and concentrated. The product is dissolved in EtOAc, filtered and recrystallized from EtOAc (895 mg, 41%). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.74 (t, J=5.27 Hz, 2H) 4.52 (t, J=5.47 Hz, 2H) 4.99 (s, 1H) 7.25 (dd, J=10.16, 8.79 Hz, 1H) 7.64 (dd, J=8.79, 4.49 Hz, 1H) 8.21 (s, 1H).
Reaction SMILES: [H][H].C[C@@H]1C=C2[C@](COC3CCCCO3)(CC[C@H](O)C2)[C@@H]2[C@@H]1[C@H]1[C@@](CC2)(C)[C@@H](O)CC1.C[C@@H]1C[C@@H]2[C@](COC3CCCCO3)(CC[C@H](O)C2)[C@@H]2[C@@H]1[C@H]1[C@@](CC2)(C)[C@@H](O)CC1.C[C@@H]1[C@@H]2[C@](CO)(CC[C@H](O)C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1.[OH:84][CH2:85][C@@:86]12[C@@H:103]3[C@H:94]([C@H:95]4[C@@:99]([CH2:101][CH2:102]3)([CH3:100])[C:98](=[O:104])[CH2:97][CH2:96]4)[CH2:93][CH2:92][C:91]1=[CH:90][C:89](=[O:105])[CH2:88][C@@H:87]2[CH3:106].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(O)C.C1C=CC=CC=1.C(O)CO>[OH:84][CH2:85][C@@:86]12[C@@H:103]3[C@H:94]([C@H:95]4[C@@:99]([CH2:101][CH2:102]3)([CH3:100])[C:98](=[O:104])[CH2:97][CH2:96]4)[CH2:93][CH2:92][C@H:91]1[CH2:90][C:89](=[O:105])[CH2:88][C@@H:87]2[CH3:106]
Reactant: [H][H]
Reactant: C[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Agent: C[C@@H]1C=C2C[C@@H](O)CC[C@]2(COC2CCCCO2)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: C[C@@H]1C[C@H]2C[C@@H](O)CC[C@]2(COC2CCCCO2)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CC[C@H](O)C[C@H]12
Solvent: CCO
Solvent: CO
Solvent: OCCO
Product: C[C@H]1CC(=O)C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO

Procedure:
Hydrogenation of 19-hydroxy-5-androstenes by means of 10% palladium on charcoal results in good yields of the corresponding 19-hydroxy-5α-androstanes. Suitable steroid substrates which fulfill the 5-ene requirement for stereoselectivity during the reduction include 3β,19-dihydroxy-5-androstenes, 19-hydroxy-5-androsten-3-ones, 19-hydroxy-5-androsten-3-one 3-cyclic ethyleneketal and 3-alkoxy-3,5-androstadien-19-ols. Typical reduction conditions utilize 2-10parts of the steroid substrate to 1 part catalyst with methanol or ethanol as solvent and hydrogen pressures ranging from 1 to 3 atmospheres. In this manner 1β,17α-dimethyl-5-androstene-3β,17β,19-triol, 7α-methyl-19-tetrahydropyranyloxy-5-androsten-3β,17β-diol and 6α-methyl-3β,19-dihydroxy-5-androsten-17-one are reduced to 1β,17α-dimethyl-5α-androstane-3β,17β,19-triol, 7α-methyl-19-tetrahydropyranyloxy-5α-androstan-3β,17β-diol and 6α-methyl-3β,19-dihydroxy-5α-androstan-17-one, respectively. 19-Hydroxy-1α-methyl-4-androstene-3,17-dione is converted to its cyclic ethyleneketal by heating at reflux temperatures with p-toluenesulfonic acid and ethyleneglycol in benzene. The ketal which forms is then reduced and hydrolyzed to form 19-hydroxy-1α-methyl-5α-androstan-3,17-dione. 17β,19-Di(trimethylsiloxy)-4-androsten-3-one can be converted to the methyl enol ether by the action of trimethylorthoformate, p-toluenesulfonic acid and methanol in tetrahydrofuran. The 3-methoxy-3,5-diene which forms is then catalytically reduced to yield 17β,19-di(trimethylsiloxy)-5α-androstan-3-one. The ethylenol ether of 19-hydroxy-4-androsten-3,17-dione acetate can also be reduced to yield 19-hydroxy-5α -androstane-3,17-dione acetate.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[N:4]=[C:5]2[C:14]3[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19](OC)=[O:20])=[CH:12][C:11]([O:23][CH3:24])=[CH:10][C:9]=3[NH:8][C:7](=[O:25])[C:6]=12.[NH3:33]>CO>[NH2:1][C:2]1[N:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[N:4]=[C:5]2[C:14]3[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]([NH2:33])=[O:20])=[CH:12][C:11]([O:23][CH3:24])=[CH:10][C:9]=3[NH:8][C:7](=[O:25])[C:6]=12
Reactant: N
Reactant: COC(=O)CCCOc1cc(OC)cc2[nH]c(=O)c3c(N)n(-c4ccccc4C)nc3c12
Solvent: CO
Product: COc1cc(OCCCC(N)=O)c2c(c1)[nH]c(=O)c1c(N)n(-c3ccccc3C)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 4-{[3-amino-7-methoxy-2-(2-methylphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-9-yl]oxy}butanoate (60 mg) and 2N solution of ammonia in methanol was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified with column chromatography to obtain the target compound (37 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH2:7])(=[O:3])[CH3:2].[CH2:8]([O:10][SiH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH3:9]>C(#N)C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][Si:11]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[O:10][CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCOC(C)=O
Solvent: N#Cc1ccccc1
Product: CCO[Si](CCCOC(C)=O)(OCC)OCC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Into a 200-ml four-necked glass flask equipped with a thermometer, condenser, stirrer, and dropping funnel were introduced 46.0 g (0.46 mol) of allyl acetate and 184 μl of a 0.05M benzonitrile solution of H2PtCl6.6H2O. The contents were heated to 60° C., followed by dropwise addition of 75.6 g (0.46 mol) of triethoxysilane thereto over a period of 30 minutes. Thereafter, the mixture was reacted at 60° C. for 3 hours. The reaction product was purified by vacuum distillation (88° to 85° C./2 mmHg). Thus, triethoxysilylpropyl acetate as the objective compound was obtained in a yield of 89.2% (purity determined by gas chromatography, 99.3%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[S:29][C:28]2=[N:30][C:31]([CH3:36])=[C:32]([C:33](O)=[O:34])[N:27]2[C:26]=1[CH3:37]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:27]3[C:28]([S:29][C:25]([CH3:24])=[C:26]3[CH3:37])=[N:30][C:31]=2[CH3:36])=[O:34])=[O:10])[N:12]=1
Reactant: Cc1nc2sc(C)c(C)n2c1C(=O)O
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sc(C)c(C)n23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3,6-Trimethyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.86 min; [M+H]+=520.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[N:4][C:5](F)=[C:6]([F:19])[C:7]=1[N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:22]([NH:26][C:5]1[C:6]([F:19])=[C:7]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])[C:2]([Cl:1])=[C:3]([F:21])[N:4]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N
Reactant: O=C1c2ccccc2C(=O)N1c1c(F)c(F)nc(F)c1Cl
Solvent: CC#N
Product: CC(C)(C)Nc1nc(F)c(Cl)c(N2C(=O)c3ccccc3C2=O)c1F
Reaction time: 0.5 h

Procedure:
To 150 ml of acetonitrile was added 30.0 g of N-(3-chloro-2,5,6-trifluoropyridine-4-yl)phthalimide together with 42.2 g of t-butylamine, and the mixture was heated under reflux with stirring for 30 minutes. The solution was concentrated under reduced pressure, then 200 ml of chloroform was added, and washed with 100 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain about the title compound as colorless solid residue.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].C[Al](C)C.[CH3:9][N:10]1[C:14]([NH:15][C:16](=[O:32])[C@@H:17]([NH:25][CH2:26][C:27](OCC)=[O:28])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][C:12]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)=[N:11]1.[Cl-].[NH4+]>ClCCl>[CH2:2]([NH:4][C:27]([CH2:26][NH:25][C@@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:14]1[N:10]([CH3:9])[N:11]=[C:12]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:13]=1)=[O:32])=[O:28])[CH3:3]
Reactant: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)nn1C
Reactant: CCN
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CCNC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)nn1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
To a 25 ml flask was added ethylamine hydrochloride (245 mg, 3.00 mmole) and 7 ml of dichloromethane. Trimethylaluminum (1.0M in hexane, 6.0 ml, 6.0 mmole) was added to the solution at room temperature. After 10 min, a solution of ethyl 2-((S)-1-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylamino)acetate 17.7 (408 mg, 1.00 mmole) in 3 ml of dichloromethane was added to the reaction mixture. The reaction was stirred at room temperature overnight. After then, the solution was poured into saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed on silica gel to give 104.2 (283 mg, 70% yield) as colorless amorphous. LCMS ESI (pos.) m/e: 407 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 1H), 8.61 (d, J=6.3 Hz, 2H), 7.66 (d, J=6.2 Hz, 2H), 7.38-7.29 (m, 5H), 6.82 (s, 1H), 5.80 (brs, 1H), 3.79 (s, 3H), 3.49 (brs, 1H), 3.29-3.20 (m, 5H), 2.93 (dd, J=13.6, 8.9 Hz, 1H), 2.14 (brs, 1H), 1.07 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:16]=1)=[O:13])C1C=CC=CC=1>C1COCC1.C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:16]=1)=[O:13]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: CCO
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of tert-butyl 3-({3-(benzyloxy)-5-[(1S)-2-methoxy-1-methylethoxy]benzoyl}amino)-1H-pyrazole-1-carboxylate (23 g, 47.8 mmol) in THF (140 mL) and ethanol (140 mL) was evacuated and purged with nitrogen (×3). 10% Palladium on carbon (2.3 g, 10% w/w) was added and reaction mixture was evacuated and finally purged with hydrogen gas. Reaction mixture was left to stir at ambient temperature under a hydrogen balloon for 16-hours. Pd/C was filtered through diatomaceous earth and the filtrate concentrated in vacuo to give a white, foam (18 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11]>CC(C)=O.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: NS(=O)(=O)c1cc(CO)ccc1Cl
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cc(C=O)ccc1Cl
Reaction time: 50 h
Yield: 64.4 %

Procedure:
A solution of 2-chloro-5-(hydroxymethyl)benzenesulfonamide (696 mg, 3.14 mmol) in acetone (30 mL) was added to a round bottom flask containing MnO2 (2.73 g, 31.4 mmol). The mixture was stirred for 50 hours until the starting material was consumed, then filtered though a pad of celite. The filtrate was evaporated to afford the product (444 mg, 64%) as a white solid. MS (ES+) m/z 220 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[C:9](\[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])=[O:18])/C(OC(C)(C)C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>NC(N)=S.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:9][C:17](=[O:18])[C:19]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:25]1
Reactant: CC(C)(C)OC(=O)/C(=C/c1ccccc1Cl)C(=O)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(N)=S
Solvent: Cc1ccccc1
Product: O=C1C[C@H](c2ccccc2Cl)Oc2ccccc21
Yield: 73.4 %

Procedure:
Prepared according to general procedure using (E)-tert-butyl 3-(2-chlorophenyl)-2-(2-hydroxyphenylcarbonyl)prop-2-enoate (36 mg, 0.10 mmol), thiourea catalyst III (7 mg, 0.010 mmol) in 1.0 mL toluene for 36 h at −25° C. and p-toluenesulfonic acid (10 mg, 0.05 mmol) for 50 h. Purification via column chromatography with 10% EtOAc/hexanes afforded 19 mg (67%) of 11 as a white solid in 88% ee. Analytical data match those reported in the literature.6
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:30][C:29]([CH3:32])([CH3:31])[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([OH:35])=O)[CH:27]=4)[NH:22]3)[CH:18]=[N:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.CN(C)CCCN=C=NCC.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:30][C:29]([CH3:31])([CH3:32])[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:35])[CH:27]=4)[NH:22]3)[CH:18]=[N:19][CH:20]=2)[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCN(c3cncc(C4CC(C)(C)c5cc(C(=O)O)ccc5N4)c3)CC2)c(C)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(N2CCN(c3cncc(C4CC(C)(C)c5cc(C(=O)NS(C)(=O)=O)ccc5N4)c3)CC2)c(C)c1
Yield: 30 %

Procedure:
A mixture of 2-{5-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-pyridin-3-yl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol), methane sulfonamide (60 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-(2-{5-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-pyridin-3-yl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-methanesulfonamide (34.5 mg, 30%) as a light yellow solid: MS (ESI) M+1=548.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[N:43]=[N:44][N:45]([C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:46]=2)=[CH:32][CH:31]=1.BrCC1C=CC(C2C=CC=CC=2C2C=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)N=2)=CC=1>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[N:43]=[N:44][N:45]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH:46]=3)=[CH:34][CH:35]=2)[C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1
Agent: BrCc1ccc(-c2ccccc2-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nn3)cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step I) and 4-bromomethyl-2'-(1-triphenylmethyl-1,2,3-triazol-4-y)-1,1'-biphenyl and 4-bromomethyl-2'-(2-triphenylmethyl-1,2,3-triazol-4-yl)-1,1'-biphenyl by the procedure described in Example 2, Step E.
Reaction SMILES: [CH3:1][N:2]([CH3:45])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:44])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:29]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:27]4[C:22](=[CH:23][C:24]([C:36]5[O:40][C:39]([C:41](O)=[O:42])=[CH:38][CH:37]=5)=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][N:2]([CH3:45])[C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:29]=[C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[C:27]4[C:22](=[CH:23][C:24]([C:36]5[O:40][C:39]([C:41]([N:50]6[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]6)=[O:42])=[CH:38][CH:37]=5)=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:15]=2)=[O:44])=[CH:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(-c5ccc(C(=O)O)o5)cc4n3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(-c3ccc4c(N5CCOCC5)nc(-c5ccc(NC(=O)Nc6ccc(C(=O)N(C)C)cc6)cc5)nc4c3)o2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.1 %

Procedure:
To a 50 mL round bottom flask, 5-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)furan-2-carboxylic acid (0.1 g, 0.00016 mol; Example 10) and N-methyl piperazine (0.024 g, 0.00024 mol) in DMF (5 mL) was added. To the flask, HATU (0.153 g, 0.0004 and TEA (0.067 mL, 0.00048 mol) were added. The reaction mass was stirred at room temperature for 12 h. To the reaction mass, ice cold water was added to provide the solid. The obtained solid was collected by filtration. The crude product was purified by column chromatography using 60-120 silica gel and 5% MeOH in chloroform. The solid was washed with MeOH and filtered to yield the desired product [0.01 g, 9%]. 1H NMR (300 MHz, DMSO-d6): δ 9.11 (s, 1H), 9.05 (s, 1H), 8.43 (d, J=8.4 Hz, 2H), 8.14 (s, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.43 (d, J=3.3 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.16 (d, J=3.3 Hz, 1H), 3.82-3.54 (m, 16H), 2.94 (s, 6H), 2.39 (s, 3H). LC-MS (ESI): Calculated mass: 688.3; Observed mass: 689.3 (RT: 0.10 min).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:31]=[CH:30][CH:29]=[C:25]([C:26](O)=[O:27])[C:24]=1[C:32](O)=[O:33])([O-:22])=[O:21].C(N(C(C)C)CC)(C)C.C(N=C=NC(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:32](=[O:33])[C:24]4[C:25](=[CH:29][CH:30]=[CH:31][C:23]=4[N+:20]([O-:22])=[O:21])[C:26]3=[O:27])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3cccc([N+](=O)[O-])c3C1=O)OC2
Reaction time: 0 h

Procedure:
In a 4-ml scintillating vial, a solution of the above 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (63 mg, 0.2 mmol) in tetrahydrofuran (2.0 ml) was treated with 3-nitro-phthalic acid (66 mg, 0.3 mmol), diisopropylethylamine (190 μl, 1.1 mmol), and 1,3-diisopropyl-carbodiimide (120 μl, 0.77 mmol). The reaction mixture was shaken vigorously for 10 seconds before being stirred at 50° C. for 43 hours and at room temperature for 20 h. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with 0.5N aqueous hydrochloric acid (25 ml), saturated sodium bicarbonate (25 ml), and brine (25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo affording crude 2-amino-5-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) 4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=O.C(O)(=O)C(O)=O.[CH2:25]([NH:27][NH2:28])[CH3:26].COCCO.C(O)(=O)C>CCCCCC.CCOC(C)=O>[CH2:25]([N:27]1[C:3](=[O:18])[C:4]([CH3:16])([CH3:17])[C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:28]1)[CH3:26]
Reactant: CCNN
Reactant: COC(=O)C(C)(C)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(O)C(=O)O
Solvent: CCCCCC
Solvent: COCCO
Solvent: CCOC(C)=O
Product: CCN1N=C(c2ccc([N+](=O)[O-])cc2)C(C)(C)C1=O

Procedure:
A mixture of 1.00 g (4 mmol) of 2,2-dimethyl-3-(4-nitrophenyl)-3-oxopropionic acid methyl ester (Yang, C.-Y.; Wnek, G. E., Polymer, 1992, 33, 4191-4196), 3.00 g (20 mmol) of ethylhydrazine oxalate, 8 mL of 2-methoxyethanol, and 4 mL of glacial acetic acid was stirred under nitrogen at gentle reflux for 24 hours. The cooled solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The ethyl acetate phase was washed with additional water and then with saturated aqueous sodium chloride solution. The organic solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 703 mg (67%) of light yellow crystals, mp 121-122° C.; homogeneous by TLC in 2:1 hexane-EtOAc. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e=232.1 (M−Et), 265.1 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].Cl[C:20]1C=CC(S(C)(=O)=O)=CC=1C(O)=O.N1CCCCC1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:20]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNCC1
Product: CS(=O)(=O)c1ccc(N2CCCCC2)c(C(=O)O)c1
Yield: 78 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example Y) from 2-Chloro-5-methanesulfonyl-benzoic acid and piperidine and obtained in 78% yield. MS (m/e): 282.0 (M−H+100%)