Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH:22]=[O:23].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[S:18][C:17]5[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:11]=4[CH:10]=[N:9]3)[C:3]=2[CH:22]=[O:23])=[CH:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 70 °C
Yield: 53 %

Procedure:
A round bottom flask was charged with 124a, 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101 l (271 mg, 0.58 mmol), PdCl2(dppf) (50 mg, 0.06 mmol), K3PO4.3H2O (323 mg, 1.16 mmol), THF (15 mL), and H2O (5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 70° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 124b as a yellow solid (200 mg, 53%). LCMS: [M+H]+ 651
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:10]=[C:9]([S:24][CH3:25])[N:8]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]2)[N:10]=[C:9]([S:24]([CH3:25])=[O:39])[N:8]=1
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(SC)nc1N1CCC(O)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(S(C)=O)nc1N1CCC(O)CC1
Reaction time: 1 h

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-methylthiopyrimidine (prepared in the above (4)) 121 mg in chloroform 3 ml is dropped a solution of m-chloroperbenzoic acid 54 mg in chloroform 4 ml on an ice bath over a period of 15 minutes, and the mixture is stirred for 1 hour. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1yl)-2-methylsulfinylpyrimidine as a colorless caramel.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([Cl:18])[CH:9]=2)=[CH:6][N:7]=1.Cl[CH:20]([CH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[CH:34]2)[CH:21](N1C(=O)CCC1=O)O>C(O)CCC>[Cl:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:20]([CH2:30][C:31]4[CH:32]=[C:33]5[C:38](=[CH:39][CH:40]=4)[N:37]=[CH:36][CH:35]=[CH:34]5)=[CH:21][N:1]=3)[N:4]=2)[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1Cl
Solvent: CCCCO
Product: COC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1Cl
Temperature: 110 °C
Reaction time: 22 h
Yield: 66.6 %

Procedure:
The mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)-2-chlorobenzoate (Step 2, 0.840 g, 3.17 mmol) and 1-(2-chloro-1-hydroxy-3-quinolin-6-ylpropyl)pyrrolidine-2,5-dione (1.11 g, 3.49 mmol, Example 1, Step 7) in 1-butanol (11.6 mL) was stirred at 110° C. for 22 h. The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate and hexane to yield the desired product (0.908 g). The mother liquor was concentrated to half volume. The precipitate was collected by filtration and washed with ethyl acetate and hexane to afford additional desired product (0.342 g). The total product obtained was 1.10 g (80.6%). LCMS (M+H)+: m/z=430.0/431.9.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:12]>ClCCl>[Br:12][CH2:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrP(Br)Br
Reactant: Cc1nc(Cl)ccc1CO
Solvent: ClCCl
Product: Cc1nc(Cl)ccc1CBr
Temperature: 0 °C

Procedure:
(6-Chloro-2-methylpyridin-3-yl)methanol (500 mg, 3.17 mmol) was taken up in dichloromethane (9.1 mL) and cooled to 0° C. Phosphorus tribromide (0.6 mL, 6.35 mmol) was added dropwise, and the reaction was allowed to warm to room temperature overnight. The reaction was then quenched by slow addition of saturated aqueous sodium bicarbonate, followed by solid sodium carbonate to obtain pH>7. The mixture was extracted with dichloromethane two times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was performed via silica gel chromatography (0-40% ethyl acetate in hexane) to yield the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=2[N:16]=1)(=[O:28])=[O:27]
Reactant: O=C1CCc2ccc(OCCCCO)nc2N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCOc1ccc2c(n1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
A mixture of intermediate 11 (140 mg, 0.593 mmol), Et3N (240 mg, 2.37 mmol) and methylsulfonyl chloride (102 mg, 0.89 mmol) was dissolved in DCM and the solution was stirred for 6 h at rt. The solution was then washed with water, brine, and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo to give 4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yloxy)butyl methanesulfonate (intermediate 12) (180 mg, 96%) as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=1>C(O)(C)C>[ClH:2].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:20]([F:25])[CH:19]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Yield: 49.2 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (147 mg, 0.56 mmol), (prepared as described for the starting material in Example 2), and 4-chloro-2-fluoroaniline (82 mg, 0.56 mmol) in isopropanol (7 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-2-fluoroanilino)-6,7-dimethoxyquinazoline hydrochloride (102 mg, 49%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:27].S(=O)(=O)(O)O.Cl([O-])=O.[Na+]>O.C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:16]=1)[C:14]([OH:27])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: COc1cc(-c2noc(C)n2)c(C=O)cc1OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1cc(-c2noc(C)n2)c(C(=O)O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzaldehyde (reference example 15-1) (5.38 g), dimethyl sulfoxide (5.89 mL), concentrated sulfuric acid (0.506 mL), water (8 mL) and acetonitrile (41 mL) was added a mixture of sodium chlorite (2.25 g) and water (10 mL). After stirring at room temperature for 30 minutes, water was added to the mixture. The solid was collected by filtration to give the title compound (3.58 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCCl>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:27][CH2:28]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](NS(C)(=O)=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 17 h

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine (47 mg, 0.108 mmol) and 1,2-dichloroethane (4 ml). To the stirred solution was added methanesulfonyl chloride (10 μm, 0.12 mmol), triethylamine (30 μl, 0.22 mmol) and 4-dimethylaminopyridine (catalytic amount). The solution was stirred for 17 hr then partitioned between aqueous sodium hydroxide (5 ml, 0.2M) and dichloromethane (5 ml). The aqueous phase was extracted with dichloromethane (2×5 ml) and the combined organic layers were washed with brine (8 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was adsorbed onto silica gel and purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, gradient elution using 1:9, 1:4, then 1:3, v/v) to give the title compound (39 mg, 70%) which solidified on standing. δH(CDCl3) 0.17 (6H, s), 0.23 (6H, s), 0.97 (9H, s), 1.00 (9H, s), 1.53 (2H, m), 1.71 (4H, m), 1.94 (2H, m), 2.85 (1H, m), 2.99 (3H, s), 3.78 (1H, m), 4.83 (1H, d), 6.28 (1H, d), 6.42 (1H, dd), 6.97 (1H, d).
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[Cl:8].[N:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[Cl:8][C:4]1[N:3]([O:2][C:15]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:16])[CH:7]=[CH:6][N:5]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: On1ccnc1Cl
Agent: Cl
Product: O=C(On1ccnc1Cl)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-2-chloroimidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (54%, oil).
Reaction SMILES: SCC(C(CS)O)O.[CH3:9][O:10][C:11](=[O:25])[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([S:22]C#N)[CH:19]=[CH:18][C:16]=2[N:17]=1>O.C(O)C.P([O-])(O)(O)=O.[K+]>[CH3:9][O:10][C:11](=[O:25])[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([SH:22])[CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: COC(=O)Nc1nc2ccc(SC#N)cc2s1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COC(=O)Nc1nc2ccc(S)cc2s1
Temperature: 20 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
a solution of 5 mg of potassium dihydrogen phosphate in 1.1 cm3 of water at 20° C., followed by 480 mg of DL-dithiothreitol, are added to a white suspension of 280 mg of methyl(6-thiocyanato-1,3-benzothiazol-2-yl)carbamate in 11 cm3 of ethanol at 20° C. The white suspension is stirred for 18 h at reflux. The reaction mixture is cooled to 20° C., then 10 cm3 of water are added and the mixture is stirred for 15 minutes. The precipitate is spin-filter-dried and then washed with large volumes of water. 231 mg of methyl(6-sulphanyl-1,3-benzothiazol-2-yl)carbamate are obtained in the form of a cream powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21]([OH:23])=O)=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[NH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([NH:34][C:21]([C:5]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[O:9])[N:6]=2)=[O:23])[CH:36]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)Nc2cccnc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with 3-aminopyridine, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 538.2 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:8][C:7]1[C:2]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1Cl
Reactant: N#CC1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC1(c2ncccc2F)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a 0° C. solution of 2-chloro-3-fluoropyridine (80.0 g, 611 mmol, 1.0 equiv) and cyclobutane carbonitrile (49.5 g, 611 mmol, 1.0 equiv) in toluene (500 mL) was added sodium hexamethyldisilazide (2.0 M in THF, 306 mL, 612 mmol, 1.0 equiv) in a dropwise manner. The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was then quenched with water (500 mL), and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (2×300 mL), and the combined organic phases were washed with saturated brine solution (2×400 mL), dried over Na2SO4, concentrated to give a crude yellow oil, and chromatographed with silica gel (2-10% EtOAc/hex) to give 1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (88 g, 83%) as a pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[N:14]([CH:15]=2)[N:13]=[CH:12][N:11]=[C:10]3O)[CH:2]=1.O=P(Cl)(Cl)[Cl:19].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:19][C:10]1[C:9]2=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:15][N:14]2[N:13]=[CH:12][N:11]=1
Reactant: Oc1ncnn2cc(-c3cccnc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ncnn2cc(-c3cccnc3)cc12
Temperature: 100 °C
Yield: 33.2 %

Procedure:
To a suspension of 6-(pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (100 mg, 0.30 mmol) in 10 mL of toluene were added POCl3 (0.18 mL, 1.88 mmol) and DIEA (0.09 mL, 0.5 mmol). The suspension was heated at 100° C. for 7 h. After cooling down, the excess POCl3 was removed under reduced pressure. The residue was suspended in EtOAc, and then neutralized with sat. NaHCO3. The organic layer was then washed with brine and dried over MgSO4. After filtration and concentration, the residue was purified by flash column chromatography to afford the title compound (23 mg, 33%). MS(ESI+) m/z 231.2/233.2 (M+H)+.
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[C:8]([S-:10])#[N:9].[K+]>CC(C)=O>[CH3:6][C:2]([S:10][C:8]#[N:9])([CH3:7])[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)C(C)(C)Br
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)C(C)(C)SC#N

Procedure:
16.5 g. (0.1 mol) of 3-bromo-3-methyl-2-butanone and 11.6 g. (0.12 mol) of potassium rhodanide were refluxed for 1-2 hours in 150 ml. of anhydrous acetone. After cooling, the separated potassium bromide was filtered under suction, back-washed with a small amount of acetone and evaporated to dryness in vacuo at 50° C. The residue was taken up in 200 ml. of ether and washed three times with 100 ml. of water. The ether phase was dried over sodium sulfate and evaporated to dryness in vacuo. The crude product was fractionated on a short Vigreux column to yield 3-methyl-3-thiocyanato-2-butanone, b.p. (0.04 mm), 52° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:3].[P:25]([O:30]C)([O:28][CH3:29])[O:26][CH3:27]>>[CH2:5]([O:4][C:2]([P:25](=[O:30])([O:28][CH3:29])[O:26][CH3:27])=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: COP(OC)OC
Reactant: CCCCCCCCCCCCCCCCCCCCOC(=O)Cl
Product: CCCCCCCCCCCCCCCCCCCCOC(=O)P(=O)(OC)OC
Reaction time: 8 h
Yield: 97 %

Procedure:
1-Eicosanyl chloroformate (6.0 g, 16.6 mmol) was added slowly to refluxing P(OMe)3 30 (mL), and after 2 hours the mixture was left at room temperature overnight. Excess P(OMe)3 was removed by vacuum distillation, and the remaining white solid was collected, washed with cold hexane, and recrystallized from hexane to obtain colorless crystals from which traces of hexane were not fully removed (7.0 g, 97% yield); mp 53-54° C.; TLC: Rf 0.39 (silica gel, 98:2 CHCl3—MeOH); IR (KBr): υ 2950, 2915, 1705, 1540, 1280, 1220 cm−1; 1H NMR (CDCl3) δ0.8-1.8 (m, >39H, CH3(CH2)18), 3.9 (d, 6H, P(OCH3)2), 4.3 (t, 2H, CH2O). Anal. Calcd. for C23H47O5P.0.15C6H14: C, 64.13, H, 11.08; P, 6.92. Found: C, 63.91; H, 10.91; P, 6.62.
Reaction SMILES: [CH2:1]([CH:3]1[NH:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]([NH2:15])[CH2:5][CH2:4]1)[CH3:2].C([C@@H]1N[C@@H](C2C=CC=CC=2)[C@@H](N)CC1)C.C([C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1)C.[CH3:46][O:47][C:48]1[CH:57]=[C:56]2[C:51]([N:52]([CH3:60])[C:53](=[O:59])[CH:54]3[CH2:58][CH:55]32)=[CH:50][C:49]=1[CH:61]=O>>[CH2:1]([CH:3]1[NH:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]([NH:15][CH2:61][C:49]2[CH:50]=[C:51]3[C:56](=[CH:57][C:48]=2[O:47][CH3:46])[CH:55]2[CH2:58][CH:54]2[C:53](=[O:59])[N:52]3[CH3:60])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCC(N)C(c2ccccc2)N1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)C1CC21
Agent: CC[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Agent: CC[C@H]1CC[C@H](N)[C@H](c2ccccc2)N1
Product: CCC1CCC(NCc2cc3c(cc2OC)C2CC2C(=O)N3C)C(c2ccccc2)N1

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-Ethyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S)-6-Ethyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-Ethyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde [or (1S,1aR)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde or (1R,1aS)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde]. Melting Point: 231–234° C. (dec); 1H-NMR (dihydrochloride, 400 MHz, CD3OD): δ 0.48 (app. q, J=5.0 Hz, 1H), 1.02 (t, J=7.5 Hz, 3H), 1.64 (ddd, J=4.2, 9.1, 9.1 Hz, 1H), 1.70–1.85 (comp, 3H), 2.21 (ddd, J=5.0, 7.5, 9.5 Hz, 1H), 2.35–2.50 (comp, 3H), 2.61 (ddd, J=8.3, 8.3, 5.5 Hz, 1H), 3.28 (s, 3H), 3.61 (m, 1H), 3.71 (s, 3H), 4.00 (m, 1H), 4.14 (ab q, J=13.3, 6.2 Hz, 2H), 5.12 (d, J=4.97 Hz, 1H), 7.09 (d, J=12.9 Hz, 2H), 7.59–7.60 (m, 3H), 7.80–7.82 (m, 2H).
Reaction SMILES: [CH2:1]([B:5]([OH:7])[OH:6])[CH2:2][CH2:3][CH3:4].O[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]O.O[C@H]([C@@H](O)C(N(C)C)=O)C(N(C)C)=O>ClCCl.[Cl-].[Na+].O>[CH2:1]([B:5]1[O:7][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCB(O)O
Reactant: OCCNCCO
Agent: CN(C)C(=O)[C@H](O)[C@@H](O)C(=O)N(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCB1OCCNCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(But-1-yl)-tetrahydro-4H-1,3,6,2-dioxazaborocine [CAS 92527-13-4] (3 g, 17.5 mmol), which was prepared from n-butylboronic acid and 2-(2-hydroxy-ethylamino)-ethanol [CAS 111-42-2] as reported in Organic Synthesis, 1998, 76, 86-96, and (2R,3R)-2,3-dihydroxy-N,N,N′,N′-tetramethyl-butanediamide [CAS 26549-65-5] (9.85 g) were dissolved in anhydrous dichloromethane (160 mL) under N2, Brine (25 mL) was added. The resulting mixture was stirred at room temperature for about 16 hours. The two layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with 50 mL brine, dried over MgSO4, filtered and concentrated in vacuo to provide the title compound as an oil.
Reaction SMILES: [NH2:1]CC1(CC2CC2)CCN(S(NCC)(=O)=O)CC1.Cl[C:20]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:21]=1[C:22](Cl)=[O:23]>>[F:29][C:28]1[CH:20]=[C:21]([C:25]([F:30])=[CH:26][CH:27]=1)[C:22]([NH2:1])=[O:23]
Reactant: CCNS(=O)(=O)N1CCC(CN)(CC2CC2)CC1
Reactant: O=C(Cl)c1c(F)ccc(F)c1Cl
Product: NC(=O)c1cc(F)ccc1F

Procedure:
4-Aminomethyl-4-(cyclopropylmethyl)-N-ethylpiperidine-1-sulfonamide (I-10) was treated with 2-chloro-3,6-difluorobenzoyl chloride according to the procedure outlined above to afford 2-chloro-N-{[4-cyclopropylmethyl)-1-[(ethylaminosulfonyl)]-piperidin-4-yl]methyl}-3,6-difluorobenzamide (I-12). 1H NMR (500 MHz, CD3OD): δ 7.37-7.31 (m, 1 H), 7.24-7.18 (m, 1 H), 3.53 (s, 2 H), 3.26-3.18 (m, 4 H), 3.04 (q, J=7.2 Hz, 2 H), 1.69 (t, J=5.7 Hz, 4 H), 1.37 (d, J=6.7 Hz, 2H), 1.16 (t, J=7.2 Hz, 3 H), 0.81-0.73 (m, 1 H), 0.50 (q, J=5.9 Hz, 2 H), 0.08 (q, J=4.8 Hz, 2 H); MS 450 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][NH2:16]>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([NH:15][NH2:16])[N:3]=[CH:4][N:5]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2cc(Cl)ncn2)cc1
Reactant: NN
Solvent: C1CCOC1
Product: NNc1cc(-c2ccc(Cl)cc2)ncn1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 67.3 %

Procedure:
To a stirred solution of 4-chloro-6-(4-chlorophenyl)pyrimidine (1.25 g, 5.6 mmol) in THF (10 mL) at room temperature under argon was added H2NNH2 (538 mg, 16.8 mmol). The reaction mixture was heated at 60° C. under argon for 2 h. Analysis by HPLC/MS indicated that the reaction was complete. About three fourths of the solvent was evaporated and Et2O (5 mL) was added to the resulting suspension. After stirring at room temperature for 20 min, solid was collected by filtration and further washed with Et2O (15 mL), then dried under vacuum to obtain 831 mg of the title compound as a white solid. HPLC/MS: retention time=1.88 min, [M+H]30 =221.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)[C:33](=[O:36])[CH2:34][CH3:35]>>[CH3:44][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:37]1[CH:38]=[CH:39][C:40]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:42][CH:43]=1)[C:33](=[O:36])[CH2:34][CH3:35]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCC(=O)N(CCN(C)C)c1ccc(N)cc1
Product: CCC(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-propionyl-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H32N4O4