Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[F:40][C:41]1[CH:42]=[C:43]([CH:52]2[CH2:57][CH2:56][C:55](=O)[CH2:54][CH2:53]2)[CH:44]=[CH:45][C:46]=1[O:47][C:48]([F:51])([F:50])[F:49]>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:55]1[CH2:54][CH2:53][CH:52]([C:43]2[CH:44]=[CH:45][C:46]([O:47][C:48]([F:49])([F:51])[F:50])=[C:41]([F:40])[CH:42]=2)[CH2:57][CH2:56]1
Reactant: O=C1CCC(c2ccc(OC(F)(F)F)c(F)c2)CC1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1cc(C2CCC(=CCC3OCCCO3)CC2)ccc1OC(F)(F)F
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (9.1 g, 20 mmols), followed by adding tetrahydrofuran (100 ml), suspending, stirring under ice cooling till the liquid temperature reached 10° C. The resulting reaction mixture was added potassium t-butoxide (2.2 g, 20 mmols) followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(3-fluoro-4-trifluoromethoxyphenyl)cyclohexanone (5.5 g, 20 mmols) over 30 minutes from the dropping funnel, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure, and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(3-fluoro-4-trifluoromethoxyphenyl)cyclohexane.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[BrH:8].[Br:9][CH2:10][CH2:11][NH2:12]>C(O)C>[BrH:9].[BrH:8].[N:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:10][CH2:11][NH2:12])=[CH:3][CH:4]=1
Reactant: Sc1ccncc1
Reactant: NCCBr
Agent: Br
Solvent: CCO
Product: NCCSc1ccncc1
Yield: 82 %

Procedure:
A solution of 32.72 g of 4-mercaptopyridine and 61.0 g of 2-bromoethanamine hydrobromide in 200 ml of absolute ethanol was heated to reflux under an argon atmosphere for 2 hours. After cooling the precipitated product was collected and washed with ethanol to give 76.31 g of crude 2-(4-pyridylthio)ethanamine dihydrobromide, mp 250°-254° C. Recrystallization from ethanol (1500 ml) and water (150 ml) with a charcoal treatment afforded 63.09 g (68%) of 2-(4-pyridylthio)ethanamine dihydrobromide, mp 265°-268° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8](Cl)[N:7]=[CH:6][N:5]=1)([OH:3])=[O:2].[CH3:11][NH:12][CH3:13]>>[C:1]([C:4]1[CH:9]=[C:8]([N:12]([CH3:13])[CH3:11])[N:7]=[CH:6][N:5]=1)([OH:3])=[O:2]
Reactant: CNC
Reactant: O=C(O)c1cc(Cl)ncn1
Product: CN(C)c1cc(C(=O)O)ncn1
Reaction time: 72 h

Procedure:
A 40% aqueous dimethylamine solution (2000 cc) is added to 4-carboxy-6-chloropyrimidine (93.6 g). The mixture is allowed to stand for 3 days and then concentrated to dryness under reduced pressure. The residue is dissolved in water (300 cc). The solution is made alkaline by the addition of sodium bicarbonate powder to a pH of 8 to 9. The solution is then extracted with diisopropyl ether (1000 cc). The aqueous phase is acidified with 12N hydrochloric acid to a pH of 2 to 3. The precipitate is filtered off, washed with ice-water (30 cc) and then with isopropanol (120 cc). 4-Carboxy-6-dimethylaminopyrimidine (73.6 g), melting at 250° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6](B1OC(C)(C)C(C)(C)O1)=[CH:5]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:29][C:30]1[CH:35]=[C:34]([N:36]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:33]2[N:53]=[CH:54][C:55](I)=[C:32]2[N:31]=1>O1CCOCC1.O>[Cl:29][C:30]1[CH:35]=[C:34]([N:36]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:42])[CH3:43])[N:33]2[N:53]=[CH:54][C:55]([C:6]3[CH:7]=[N:8][C:9]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=4)=[C:32]2[N:31]=1
Reactant: CC1(C)OB(c2cnc3ccc(F)cc3c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(I)cnn12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (3.65 mmol, 996.4 mg), K3PO4 (9.12 mmol, 1933.6 mg), and PdCl2(dppf)CH2Cl2 (0.30 mmol, 248 mg) was added to a solution of 5-chloro-3-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (3.04 mmol, 1684.3 mg) in dioxane (18 mL) and H2O (3 mL). The resulting solution was stirred at 80° C. under argon overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded 5-chloro-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine: LCMS tR=3.36 Min (5 min run, UV254nm). Mass calculated for, M+ 581.2, observed LC/MS m/z 582.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH:11]([OH:18])[CH2:12]OS(C)(=O)=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C(O)(C)C>[CH:19]([NH:22][CH2:12][CH:11]([OH:18])[CH2:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N
Reactant: COc1ncccc1OCC(O)COS(C)(=O)=O
Solvent: CC(C)O
Product: COc1ncccc1OCC(O)CNC(C)C

Procedure:
22 g of crude 2-methoxy-3-(3'-methanesulphonyloxy-2'-hydroxy-propoxy)-pyridine, 50 ml of isopropylamine and 150 ml of isopropanol are heated for 16 hours under reflux. After working up analogously to Example 14, 3-(3'-isopropylamino-2'-hydroxypropoxy)-2-methoxy-pyridine is obtained, which melts at 50°-65° C. after recrystallisation from ether-pentane. After reaction with half the equivalent amount of fumaric acid, the neutral fumarate of melting point 146°-147° C. (recrystallised from acetone) is obtained.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:28])[CH:20](Br)[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1>[CH3:17][O:18][C:19](=[O:28])[CH:20]([N:11]1[C:10](=[O:14])[CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[N:12]1)[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=c1cc(Oc2ccccc2)cn[nH]1
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
A solution of 5-phenoxy-2H-pyridazin-3-one (1.42 g, 7.54 mmol) in tetrahydrofuran (37.7 mL, 0.2M) cooled to 0° C. was treated with a 60% suspension of sodium hydride in mineral oil (362 mg, 9.05 mmol). The reaction stirred at 0° C. for 5 min and then at 25° C. for an additional 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 1.95 g, 8.30 mmol). The reaction was then warmed to 50° C., where it stirred for 18 h. After this time, the reaction was partitioned between water (300 mL) and methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (Isco 40 g, 20% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionic acid methyl ester (1.72 g, 66%) as a clear oil; ES+-HRMS m/e calcd for C19H22N2O4 [M+H+] 343.1653, found 343.1652.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].S(O)(O)(=O)=O.[CH3:17][S:18][C:19](=[NH:21])[NH2:20]>ClCCl>[CH2:5]([O:4][C:2]([NH:21][C:19](=[N:20][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[S:18][CH3:17])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CSC(=N)N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
2 ml (14.4 mol) of benzyl chloroformate are added dropwise, under vigorous stirring, to a solution of 1 g (3.60 mmol) of S-methylisothiourea sulphate in 40 ml of a diphasic mixture of dichloromethane/saturated aqueous sodium bicarbonate solution (1:1). Stirring is maintained at ambient temperature for 25 hours. After which, the aqueous phase is extracted 3 times with dichloromethane. The combined organic phases are then washed with water, then dried over sodium sulphate and evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica column (DCM) in order to produce 1.06 g (82%) of product in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:5]2=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)[CH:51]=[CH:52][C:53]=1[CH3:54]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([NH:47][C:48]3[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]4[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:64])([F:65])[F:66])[CH:58]=4)[CH:51]=[CH:52][C:53]=3[CH3:54])=[O:13])[S:10][C:5]2=[N:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: O=C(O)c1cc2nc(Cl)cnc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A solution of 2-chlorothieno[3,2-b]pyrazine-6-carboxylic acid 23 (219 mg, 1.019 mmol), HATU (465 mg, 1.223 mmol) and DIPEA (0.337 mL, 2.039 mmol) in DMF (6 mL) was stirred for 15 min at rt. N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide 67 (300 mg, 1.019 mmol) was added and stirred overnight at rt and overnight at 60° C. The reaction mixture was poured out in 3% citric acid solution and the resulting precipitate was collected and washed with water to give compound 2-chloro-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 68 (389 mg, 78%). (m/z)=491 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH3:32][C:33]1[S:34][CH:35]=[C:36](/[CH:38]=[CH:39]/[C:40]2[C:41]([OH:51])=[N:42][N:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:44]=2)[N:37]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][O:29][C:5]1[CH:4]=[C:3]([CH2:2][O:51][C:41]2[C:40](/[CH:39]=[CH:38]/[C:36]3[N:37]=[C:33]([CH3:32])[S:34][CH:35]=3)=[CH:44][N:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:42]=2)[CH:28]=[CH:27][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=2)[O:12][C:13]=1[CH3:14]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: Cc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(C)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.49 g), 4-[(E)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol.hydrochloride (1.05 g), potassium carbonate (1.01 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl {4-[4-({2-methoxy-4-[({4-[(E)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (1.25 g, yield 53%) as pale-yellow crystals. melting point: 153-155° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13]2)[C:8]([C:22]2[N:23]=[C:24]3[C:30]([C:31]#[N:32])=[CH:29][N:28](COCC[Si](C)(C)C)[C:25]3=[N:26][CH:27]=2)=[CH:7][N:6]=1)(=O)=O.O1CCOCC1.[CH3:47][NH:48][CH3:49].CS(C)(=O)=O>>[CH3:47][N:48]([CH3:49])[C:5]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:13]2)[C:8]([C:22]2[N:23]=[C:24]3[C:30]([C:31]#[N:32])=[CH:29][NH:28][C:25]3=[N:26][CH:27]=2)=[CH:7][N:6]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: CNC
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CN(C)c1ncc(-c2cnc3[nH]cc(C#N)c3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a dioxane 2-[2-methanesulfonyl-4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-pyrimidin-5-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonitrile derived from step 2 above, dimethylamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to Scheme 1, step 5 to give 2-[2-dimethylamino-4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-pyrimidin-5-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carbonitrile. MS: (ES+): 442.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[C:8]([C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12][CH:11]=1)=[CH:7][CH:6]=[N:5]2.[I:20]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[I:20][C:3]1[N:4]2[N:5]=[CH:6][CH:7]=[C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[N:12][CH:11]=3)[C:9]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc2c(-c3ccnn4ccnc34)cncc2c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Ic1cnc2c(-c3cncc4ccccc34)ccnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 4-(imidazo[1,2-b]pyridazin-8-yl)isoquinoline (220 mg, 0.893 mmol) in CHCl3 (10 mL) were added N-iodo succinimide (241 mg, 1.072 mmol) and TFA (0.275 mL, 3.57 mmol) In CHCl3 (1 mL). The reaction mixture was stirred at room temperature for 2 h and quenched with saturated NaHCO3. The layers were separated and the combined organic layer was washed with water and brine, dried over Na2SO4. The crude product was purified by BIOTAGE® (30-70% EtOAc/CH2Cl2, 0.8 L) to give the product (290 mg, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 9.41 (1H, s), 8.72 (1H, s), 8.66 (1H, d, J=4.53 Hz), 8.07-8.17 (1H, m), 7.90 (1H, s), 7.71 (3H, d, J=3.02 Hz), 7.28 (3H, s), 7.26 (1H, d, J=4.53 Hz); LC/MS: Rt=1.53 min. LC/MS (Condition A): 373.08.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:13])(=[NH:12])[CH2:8][CH2:9][CH2:10][CH3:11].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25])([O-:16])=[O:15]>C1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:12][C:7](=[NH:13])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:25])([O-:16])=[O:15]
Reactant: CCCCC(=N)N
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccccc1[N+](=O)[O-]

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 150 ml. dry acetone, 13.6 g. valeramidine hydrochloride, and 16.4 g. 2-nitrophenyl isocyanate in 300 ml. benzene, there was obtained after recrystallization from ethyl alcohol 9.1 g. of the hydrochloride of 1-(2-nitrophenyl)-3-(pentanimidoyl)urea; m.p. 130°-132°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([CH2:18][N:15]2[CH2:14][CH2:13][CH:12]([C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[O:11])[CH2:17][CH2:16]2)[CH2:20]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCN(C[C@@H]2CCCNC2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCN(C[C@@H]2CCCN(Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)-1-[(3R)-piperidin-3-ylmethyl]piperidine-4-carboxamide (150 mg) and benzaldehyde (0.04 mL) in dichloromethane was added sodium triacetoxyborohydride (103 mg). The reaction mixture was stirred at room temperature for 18 hours. The reaction was incomplete so sodium triacetoxyborohydride (50 mg) was added and the mixture was stirred for 48 hours. The reaction mixture was partitioned between dichloromethane and water and the organic layer was washed with brine. The organic extract was dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in dichloromethane to give the title compound as a white solid (28 mg, 15%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([C:17]([OH:19])=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:24]O>>[CH3:24][O:18][C:17]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=1)=[O:19]
Reactant: CO
Reactant: Cc1ccc(-c2cc(C(=O)O)cc([N+](=O)[O-])c2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid (10.00 g, 0.039 mol) in methanol was added SOCl2 (5.09 g, 0.043 mol) at 0° C. The reaction mixture was allowed to warm to room temperature and was then heated to reflux for 2 hours. The solvent was removed in vacuo to afford 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester (9.72 g, 92%) as light yellow solid. MS (M+H)=273.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:13])[C:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:14]1([C@H:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:1]([NH:5][C:6](=[O:13])[C:7](=[N:22][C@@H:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:21])[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)NC(=O)C(=O)C(C)(C)C
Product: C[C@@H](N=C(C(=O)NC(C)(C)C)C(C)(C)C)c1ccccc1
Yield: 58.2 %

Procedure:
The procedure described under l) was carried out using 7.5 g of N-tert-butyl-3,3-dimethyl-2-oxo-butyramide and 15 g of (R)-1-phenylethylamine. There were isolated 6.8 g (58%) of (R)-N-tert-butyl-3,3-dimethyl-2-(1-phenylethylimino)-butyramide of boiling point 120° at 0.2 mbar. [α]=+40.9 (c=1.0, CHCl3).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])[CH:17]=1
Reactant: OCc1ccc(Cl)cc1OCC(F)(F)F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2OCC(F)(F)F)c1
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 4.43 (2H, q, J=8.0 Hz), 5.26 (2H, s), 5.79 (1H, d, J=1.6 Hz), 6.91 (1H, d, J=1.6 Hz), 7.10 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.40 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.44 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.69 (1H, d, J=5.2 Hz). [M+H] Calc'd for C18H12ClF3N4O2, 409, Found, 409.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[Cl:17])[NH:13][CH:12]=[C:11]2[CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22].[H-].[Na+].[C:26](Cl)(=[O:28])[CH3:27]>C(O)(=O)C>[C:26]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH3:6])=[C:16]([Cl:17])[CH:15]=2)[C:11]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:12]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(CCNC(C)=O)c[nH]c2cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc2c(CCNC(C)=O)cn(C(C)=O)c2cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To 30 ml. of N,N-dimethylformamide were added 210.7 mg. (0.79 mmole) of N-[2-(5-methoxy-6-chloroindol-3-yl)ethyl]acetamide (prepared as in Example 1) followed by 20.8 mg. of sodium hydride. The resulting mixture was stirred at room temperature for about one hour, and 68.2 mg. (0.06 ml.) of acetyl chloride were added. The mixture was stirred for an additional hour and then was poured into ice water containing a small amount of acetic acid. The resulting mixture was extracted with chloroform, and the extract was washed twice with saturation aqueous sodium chloride solution. The chloroform extract was dried over sodium sulfate and was concentrated in a rotary evaporator. The residue was recrystallized from benzene-ether and was vacuum-dried to obtain 108 mg. (40.8%) of the title compound, m.p. 178°-181° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:34]([O:36][C:37](=[O:42])[C:38](Br)([CH3:40])[CH3:39])[CH3:35]>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH2:22][C:38]([C:37]([O:36][CH2:34][CH3:35])=[O:42])([CH3:40])[CH3:39])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reaction time: 0.5 h

Procedure:
To 4-(5-acetyl-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1.36 g, 4.24 mmol) in THF (15 mL) at −78° C. was added 0.5M potassium bis(trimethylsilyl)amide in toluene (17 mL) and stirred for 30 min before adding 2-bromo-2-methyl-propionic acid ethyl ester (1.25 mL, 8.49 mmol) at −78° C. After overnight stirring at r.t., the reaction was quenched with 1N HCl, extracted with dichloromethane, washed with water/brine, dried over sodium sulfate, and concentrated. The product was purified using a Single Step column (7:3 hexanes:ethyl acetate) to obtain 0.458 g (25%); MS m/z 435 (M+H).