Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(Cl)(=O)C(Cl)=O.C[N:33](C=O)C>ClCCl>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:33])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CN(C)C=O
Reactant: COC1(Cc2ccccc2F)CCN(c2ccc(C(=O)O)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC1(Cc2ccccc2F)CCN(c2ccc(C(N)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of EXAMPLE 1E in dichloromethane (20 mL) was treated with oxalyl chloride (0.305 mL, 3.50 mmol) and a drop of DMF, stirred for 6 hours at room temperature, and concentrated. The resulting residue was dissolved in dichloromethane (20 mL), cooled to 0° C., treated with aqueous NH3 (3 mL), stirred for 6 hours, and partitioned between ethyl acetate and saturated aqueous sodium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried (MgSO4) and filtered. Concentration of the filtrate gave the desired product as a residue that was utilized directly in the next step without further purification. MS
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[CH3:17][N:18]([CH3:26])[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[CH3:17][N:18]([CH3:26])[C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:10]2[N:11]=[CH:12][C:7]3[CH:6]=[CH:5][C:4](=[O:16])[N:3]([CH2:1][CH3:2])[C:8]=3[N:9]=2)=[CH:21][CH:20]=1
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Reactant: CN(C)c1ccc(N)cc1
Product: CCn1c(=O)ccc2cnc(Nc3ccc(N(C)C)cc3)nc21
Temperature: 175 °C
Yield: 50 %

Procedure:
A mixture of 8-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (155 mg, 0.65 mmol) and 500 μL of 4-dimethylaminoaniline was heated at 175° C. for 10 minutes, then cooled to room temperature and partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resultant solid was washed with hexane and ethyl acetate then purified by flash chromatography eluting with ethyl acetate. The fractions containing product were concentrated and a 2:1 mixture of hexane and ethyl acetate was added to the residue. The resultant precipitate was collected by filtration to give 110 mg (50%) of 2-(4-dimethylamino-phenylamino)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 189-191° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:22])=[CH:7][CH:8]=1
Reactant: Clc1ccc(SCc2ccccn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
A suspension of 2-(((4-chlorophenyl)thio methyl) pyridine, hydrochloride (2.0 g) in methylene chloride (50 ml) at 0° C. was treated with a solution of m-chloroperoxybenzoic acid (1.7 g) in CH2Cl2 (25 ml). The mixture was allowed to warm to ambient temperature and was stirred for 5 hours. The solution was washed with saturated sodium carbonate solution and water, then dried (MgSO4). The residue was dissolved in acetone and converted into the hydrochloride with ethereal HCl. N.m.r. showed approximately 20% of starting material remaining so the material was suspended in methylene chloride (50 ml) and treated with further m-chloroperoxybenzoic acid (2×500 g). The solution was washed with saturated sodium carbonate solution and water, dried (MgSO4) evaporated and the residue was dissolved in acetone and the hydrochloride precipitated with ethereal HCl solution. Recrystallisation from acetone-ether gave the title compound as the hydrochloride (0.7 g) mp 170° C. decomp. (Found: C,49.2; H,3.8; N,4.5 C12H10ClNOS.HCl.1/4 H2O requires C,49.2; H,4.0; N,4.8%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-])=O)[C:5]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[C:4]([F:23])[CH:3]=1>C(O)(=O)C.CO.[Fe]>[NH2:9][C:6]1[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=[C:4]([F:23])[C:5]=1[C:12]1[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1c(O)c(Cl)cc(F)c1-c1ncc(C(F)(F)F)cc1Cl
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1c(O)c(Cl)cc(F)c1-c1ncc(C(F)(F)F)cc1Cl
Yield: 96 %

Procedure:
770 mg (13.7 mmol) of iron powder were added to 1.7 g (4.6 mmol) of 2-(4-chloro-2-fluoro-5-hydroxy-6-nitrophenyl)-3-chloro-5-trifluoromethylpyridine in 9 ml of glacial acetic acid and 18 ml of methanol. The reaction mixture was refluxed for 15 hours with stirring and then concentrated under reduced pressure. The residue was taken up in 100 ml of ethyl acetate. Undissolved components were then filtered off. The filtrate was washed with 20 ml of water, dried over magnesium sulfate and finally concentrated. Yield: 96%; oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12]>CC(O)(C)C>[CH3:14][O:13][C:11]([CH:10]([C:9]([O:16][CH3:17])=[O:15])[CH:3]1[C:2]([CH3:8])([CH3:1])[CH2:6][C:5](=[O:7])[CH2:4]1)=[O:12]
Reactant: COC(=O)CC(=O)OC
Reactant: CC1(C)C=CC(=O)C1
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=O)OC)C1CC(=O)CC1(C)C
Temperature: 30 °C
Reaction time: 72 h
Yield: 83.4 %

Procedure:
Under an atmosphere of argon, 11.0 mg (0.02 mmol, S/C=50) of Ru[(S,S)-Msdpen] (hexamethylbenzene), 122 μL (1.0 mmol) of 4,4-dimethyl-2-cyclopentenone, 114 μL (1.0 mmol) of dimethyl malonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 30° C. for 72 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 202 mg (83% yield) of the title compound. The optical rotation [α]D25 was +101.6 (c 1.04, CHCl3). After this was converted into an ethylene ketal derivative by the same procedure as in Example 3, the optical purity was measured by HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane: 2-propanol=97:3, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 99% ee.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 4-fluorobenzenesulfonyl chloride (564 mg). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(4-fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (937 mg).
Reaction SMILES: F[C:2]1C=C2C(=C[CH:11]=1)NC(=O)[C@H](C)N2.[C:14](=[O:40])([O-:39])[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=3)[NH:28][C:27](=[O:36])[C@@H:26]2[CH2:37]C)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:14](=[O:40])([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=3)[NH:28][C:27](=[O:36])[C@@H:26]2[CH3:37])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[O:39][CH2:2][CH3:11]
Reactant: CC[C@H]1C(=O)Nc2ccc(F)cc2N1S(=O)(=O)c1ccc(OC(=O)[O-])cc1
Reactant: C[C@@H]1Nc2cc(F)ccc2NC1=O
Product: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(F)ccc3NC(=O)[C@@H]2C)cc1

Procedure:
(3S)-6-Fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of 4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]sulfonyl}phenyl carbonate (see Example 20) to yield ethyl 4-{[(2S)-7-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]sulfonyl}phenyl carbonate. MS (ESI) m/z 409 ([M+H]+); MS (ESI) m/z 407 ([M−H]−);
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C@H:3]1CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1.N>>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][C@H:7]1[CH2:6][O:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1
Reactant: CN1C=CC=C[C@H]1CO
Reactant: Oc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN1CCC[C@H]1COc1cccnc1
Yield: 31 %

Procedure:
(S)-1-Methyl-2-pyridinemethanol was reacted with triphenylphosphine, DEAD and 3-hydroxypyridine according to the procedure outlined in Example 1a The crude product was purified by flash chromatography (2×) using (10% MeOH/CHCl3) to remove the diethyl hydrazine dicarboxylate impurity and give a yellow oil in 31% yield. MS (DCI/NH3) m/e 193 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32 (t, J=1.5 Hz, 1H), 8.22 (t, J=3 Hz, 1H), 7.24-7.2 (m, 2H), 4.14-4.05 (dd, J=9, 6 Hz, 1H), 4.00-3.93 (dd, J=9, 6 Hz, 1H), 3.243.14 (m, 1H, 2.81-2.7 (m, 1H), 2.54 (s, 3H), 2.44-2.31 (m, 1H, 2.14-2.00 (m, 1H, 1.96-1.71 (m, 3H).
Reaction SMILES: Cl.[CH:2]1([O:6][C:7]2[C:16]([C:17]3[N:18](COCC[Si](C)(C)C)[C:19]([CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:20][N:21]=3)=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:48])[N:12]3[C:43]([CH:45]2[CH2:47][CH2:46]2)=[O:44])[CH2:5][CH2:4][CH2:3]1>ClCCl.O1CCCC1>[CH:2]1([O:6][C:7]2[C:16]([C:17]3[NH:18][C:19]([CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[CH:20][N:21]=3)=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:48])[N:12]3[C:43]([CH:45]2[CH2:47][CH2:46]2)=[O:44])[CH2:5][CH2:4][CH2:3]1
Reactant: C[C@H]1CCc2c(ccc(-c3ncc(C4CCN(C(=O)OC(C)(C)C)CC4)n3COCC[Si](C)(C)C)c2OC2CCC2)N1C(=O)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H]1CCc2c(ccc(-c3ncc(C4CCNCC4)[nH]3)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Hydrogen chloride (gas) was bubbled into a solution of tert-butyl 4-(2-((S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)piperidine-1-carboxylate (0.094 g, 0.14 mmol) in dichloromethane (4 mL) and tetrahydrofuran (1 mL), and the resulting solution stirred for 1.5 h at room temperature. The reaction mixture was concentrated under vacuum, and the residue was dissolved in methanol (5 mL). The pH of the solution was adjusted to 8 with saturated aqueous sodium carbonate solution, and the resulting solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (55% to 75% acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-(5-cyclobutoxy-2-methyl-6-(5-(piperidin-4-yl)-1H-imidazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.0018 g, 3%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.71-0.78 (m, 1H), 0.82-0.99 (m, 2H), 1.13-1.18 (m, 4H), 1.21-1.41 (m, 5H), 1.55-1.65 (m, 1H), 1.75-2.21 (m, 9H), 2.32-2.48 (m, 2H), 2.89-3.11 (m, 4H), 3.31-3.34 (m, 1H), 4.16-4.21 (m, 1H), 4.70-4.81 (m, 1H), 6.97 (s, 1H), 7.26 (d, J=8.40 Hz, 1H), 7.65 (d, J=8.40 Hz, 1H). MS (ESI, pos. ion) m/z 435 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:37])[C:12]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:19]([CH3:21])[CH:20]=1)=[CH2:13])[CH3:9].C(OCC)(=O)C.[C:44]([OH:47])(=[S:46])[CH3:45]>>[CH2:8]([O:10][C:11](=[O:37])[CH:12]([CH2:13][S:46][C:44](=[O:47])[CH3:45])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:19]([CH3:21])[CH:20]=1)[CH3:9]
Reactant: C=C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)OCC
Reactant: CC(O)=S
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Triethylamine (0.234 mL, 1.68 mmol) was added to a solution of 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.68 g, 1.61 mmol) in thioacetic acid (3 mL) at 0° C. The mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic phase was washed with water, saturated NaHCO3 and brine and dried. The crude product was purified by flash chromatography (toluene/ethyl acetate, 3:1→1:2) to give pure 2-acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (489 mg, 61%) and slightly impure 2-acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (0.34 g, 43%).
Reaction SMILES: [CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]([N+:18]([O-])=O)=[C:6]([CH:15]=2)[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:2]1.C(O)C.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>[Pd].C(OCC)(=O)C>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:18][C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:17][C:16]3=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:33])=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1cc2c(cc1C=Cc1ccccn1)OCO2
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2cc3c(cc2CCc2ccccn2)OCO3)cc1
Reaction time: 0.5 h

Procedure:
2-(4,5-Methylenedioxy-2-nitrostyryl)pyridine (10.8 g., 0.04 mole) is hydrogenated on a Parr apparatus in 200 ml. of ethanol with 2.0 g. of 10% palladium on carbon as catalyst. After the reduction is complete, the mixture is filtered and the solvent evaporated. The residue consisting of 2-(4,5-methylenedioxy-2-aminophenethyl)pyridine is immediately dissolved in pyridine (100 ml.) and anisoyl chloride (7.5 g., 0.044 mole) added. The solution is stirred for 30 min. A basic workup according to the procedure of Example 25 affords 10 g. of 4-methoxy-4',5'-methylenedioxy-2'-[2-(2-pyridyl)ethyl]benzanilide obtained analytically pure by crystallization from ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:21][CH:9]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:40](=[O:41])[NH:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C=Nc1ccccn1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OC(=O)Nc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(ff) In an analogous manner to that described in Example 24(m), by reacting tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-pyridyl isocyanate there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(pyridin-2-ylcarbamoyloxy)-phenyl]-piperidine-1-carboxylate as a white solid; MS: 554 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:35])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:32]=[CH:31][C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([F:30])[F:29])[CH:23]=4)=[O:20])=[C:17]([O:33][CH3:34])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:35][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39]([CH:36]2[CH2:38][CH2:37]2)=[O:40])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:32]=[CH:31][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:33][CH3:34])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Yield: 26.4 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide (Intermediate-39, 0.050 g, 0.10 mmol), cyclopropane carbonyl chloride (0.016 g, 0.15 mmol), DIPEA (2.0 mL) and THF (2 mL) to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.68 (d, J=8.7 Hz, 4H), 1.60 (m, 1H), 3.95 (s, 3H), 4.34 (d, J=5.4 Hz, 2H), 7.05 (m, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.41-7.55 (m, 4H), 7.65 (d, J=9.0 Hz, 1H), 7.74 (s, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.07 (s, 1H), 8.72 (m, 1H), 10.33 (s, 1H); MS (m/z): 566.29 (M−H)−.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].Cl[C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[N:9][N:10]=1>CN(C=O)C>[NH:1]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:19])([F:20])[F:18])=[N:9][N:10]=1)[C:2]#[N:3]
Reactant: N#CN
Reactant: FC(F)(F)c1ccccc1-c1nnc(Cl)s1
Agent: [Na]
Solvent: CN(C)C=O
Product: N#CNc1nnc(-c2ccccc2C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred mixture of sodium cyanamide (0.16 g, 2.5 mmol) and anhydrous DMF (3 mL) under a nitrogen atmosphere was treated with solution of 2-chloro-5-[2-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (0.27 g, 1 mmol) in anhydrous DMF (2 mL). The mixture was stirred for 16 h at room temperature. Solvent was removed in vacuo and the residue was stirred with water (10 mL) during the addition of aqueous 2N HCl until the pH was 2. Extraction with Et2O followed by drying of the extracts and evaporation gave the desired cyanamide: yield 0.22 g (82%); MS 270 (M+)(C10H5F3N4S requires M+ 270). The product was used directly without further purification.
Reaction SMILES: O.[NH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[OH:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)C>[OH:13][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:3]2[NH:2][C:14](=[O:16])[CH3:15]
Reactant: Nc1cccc2c(O)cccc12
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1cccc2c(O)cccc12
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Into a 500 ml round bottom flask (fitted with a magnetic stirrer), a 50:50 mixture of water:ethanol was combined with 5-amino-1-naphthol (20 g, 125 mmole) until the solid was completely dissolved. The solution was warmed to boiling and to it was added acetic anhydride (14 g) and the resulting solution was stirred for 1 hour. Upon cooling, crystals of N-(5-hydroxy1-napthyl)acetamide (21 g, 84% yield) formed.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]1)[C:8]1[C:9]([CH2:14]O)=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:6]>C(Cl)Cl>[Cl:3][CH2:14][C:9]1[C:8]([N:7]([CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH2:5][CH3:6])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2CO)CC1
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2CCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (470 mg, 288 μL, 3-95 mmol) was added to a stirred solution of ethyl [trans-4-({ethyl[2-(hydroxymethyl)pyridin-3-yl]amino}methyl)cyclohexyl]acetate (132.2 mg, 0.395 mmol) in dry CH2Cl2 (10 mL) at room temperature. The reaction was stirred overnight at room temperature then quenched with pyridine (425 μL) and washed with water. The aqueous layer was extracted with CH2Cl2 (2×20 mL) an the combined extracts were dried (Na2SO4) and concentrated in vacuo to afford ethyl (trans-4-{[[2-(chloromethyl)pyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate. 1H NMR (500 MHz, CDCl3): δ 8.37 (dd, J=1.2, 4.5 Hz, 1 H); 7.51 (dd, J=1.4, 8.1 Hz, 1 H); 7.23 (dd, J 3.7, 8.3 Hz, 1 H); 4.86 (s, 2 H); 4.10 (q, J=7.1 Hz, 2 H); 3.03 (q, J=7.1 Hz, 2 H); 2.81 (d, J=7.1 Hz, 2 H); 2.14 (d, J=6.8 Hz, 2 H); 1.80-1.67 (m, 5 H); 1.42-1.29 (m, 1 H); 1.23 (t, J=7.1 Hz, 3 H); 0.99 (t, J=7.1 Hz, 3H); 0.94-0.86 (m, 4 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH2:27])[CH:22]=[CH:21]2.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.O>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH:27][C:14]([C:11]1[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:13][CH:12]=1)=[O:15])[CH:22]=[CH:21]2
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Reactant: Nn1ccc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nn1ccc2cc(F)ccc21)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (20 mL) is added to a stirred solution of 5-fluoro-indol-1-ylamine (1 mmol) and potassium carbonate (1 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt and the reaction mixture is stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (148 mg, 42%) as a solid. MS: 351 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.56 (m, H) 7.02 (m, H), 7.12-7.34 (m, 3H), 7.51 (m, H), 8.24 (d, H), 8.34 (s, H), 8.92 (br, H), 9.24 (br, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([NH:6][C:7](=O)[O:8]CC)=[C:4]([F:14])[CH:3]=1.[NH2:15]/[C:16](/[CH3:23])=[CH:17]\[C:18]([O:20]CC)=O>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([N:6]2[C:18](=[O:20])[CH:17]=[C:16]([CH3:23])[NH:15][C:7]2=[O:8])=[C:4]([F:14])[CH:3]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)Nc1ccc(Cl)cc1F
Product: Cc1cc(=O)n(-c2ccc(Cl)cc2F)c(=O)[nH]1

Procedure:
In an analogous manner, starting from ethyl 4-chloro-2-fluorocarbanilate and ethyl 3-aminocrotonate there is obtained 3-(4-chloro-2-fluorophenyl)-6-methyl-2,4(1H,3H) -pyrimidinedione. m.p. >220° C.; mass spectrum (m/e): 254 (M+), 235, 219, 17, 143, 108, 83, 68, 42;