Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([F:21])([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:22])[C:3]=1N.[N:23]1C=CC=CC=1.O1CCCC1.[Cl:34][C:35]([Cl:51])([Cl:50])[CH2:36][O:37][C:38]([NH:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](Cl)=[O:45])=[O:39]>O.C(OCC)(=O)C>[CH3:22][C:5]1[CH:6]=[C:7]([C:9]([F:21])([C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])[C:10]([F:11])([F:12])[F:13])[CH:8]=[C:2]([CH3:1])[C:3]=1[C:42]1[C:41]([NH:40][C:38]([O:37][CH2:36][C:35]([Cl:51])([Cl:50])[Cl:34])=[O:39])=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([NH2:23])=[O:45]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1N
Reactant: O=C(Nc1cccc(C(=O)Cl)c1)OCC(Cl)(Cl)Cl
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1-c1c(NC(=O)OCC(Cl)(Cl)Cl)cccc1C(N)=O
Yield: 71.2 %

Procedure:
First, to a solution prepared by adding 0.34 g of 2,6-dimethyl-4-(nonafluoro-2-butyl)aniline and 0.09 g of pyridine to 5 ml of tetrahydrofuran and stirring the resultant mixture at room temperature was added 0.33 g of 3-[(2,2,2-trichloroethoxy)carbonylamino]benzoyl chloride produced in Example 9-2. After reaction for 5 hours, ethyl acetate and water were added to the reaction solution, and a separating operation was performed. Then, an organic layer was separated and dried with anhydrous magnesium sulfate. The solution was filtered, and then the filtrate was collected, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 0.45 g (yield 71%) of the title compound as a solid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[N:18][CH:19]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:24]([O:23][CH2:22][CH2:21][O:20][C:17]1[N:18]=[CH:19][C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)=[CH:15][CH:16]=1)[CH3:25]
Reactant: COC(=O)c1ccccc1S
Reactant: CCOCCOc1ccc(C#N)cn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOCCOc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 57.3 %

Procedure:
A mixture of methyl thiosalicylate (2.96 g, 17.6 mmol), 5-cyano-2-(2-ethoxy)ethoxypyridine (3.07 g, 16.0 mmol), triethylamine (2.37 ml, 17.0 mmol) and toluene (15 ml) was refluxed under nitrogen atmosphere for 40 hrs. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (1:1, v/v) and recrystallized from acetone-ethyl acetate-isopropylether to give the titled compound (3.01 g, 57%).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[NH:26]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]1>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([N:26]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: OC1CCNC1
Solvent: CO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(N4CCC(O)C4)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 76.1 %

Procedure:
A solution of mitomycin A (50 mg) in 6 ml of anhydrous methanol was treated with 3-pyrrolidinol (13 mg) under nitrogen at room temperature. When thin-layer chromatography on silica gel (2:8 methanol-chloroform as solvent) showed that starting material no longer was present, the mixture was filtered and evaporated under reduced pressure. The residue was purified by preparative thinlayer chromatography using the same solvent system. This procedure gave 23 mg (40% yield) of the desired product having a melting point of 82°-85° C. (decomposition) and providing the following analysis:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]#[N:22].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]#[N:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc2cc(OC3CCOC3)c([N+](=O)[O-])cc2c1O
Product: N#Cc1cnc2cc(OC3CCOC3)c([N+](=O)[O-])cc2c1Cl
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 92.7 %

Procedure:
To a single-neck reaction flask (100 ml) were added 4-hydroxy-6-nitro-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile (1.8 g, 3 mmol) and POCl3 (10 mL) under argon atmosphere. The mixture was warmed to the temperature of 105° C. The reaction mixture was stirred for 2.5 hr. Then the reaction was stopped. The resultant mixture was rotary-evaporated to dryness. DCM (20 mL) was added to dissolve the resultant mixture. The solution was poured into a cooled mixture solution of DCM (200 mL) and saturated K2CO3 solution (60 mL). The resultant mixture was stirred for 10 min. The solution was extracted and the aqueous layer was discarded. The DCM layer was washed with water (150 mL) and staturated NaCl solution (150 mL), successively. The resultant substance was dried over MgSO4 for half-hour, filtered, rotary-evaporated to dryness, and dried in vacuo to give a yellow solid (1.771 g). Yield: 92.7%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]([N:13]2[CH2:17][CH:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].CO>O1CCCC1.O>[C:3]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]([N:13]2[CH2:17][CH:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(COC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CC1CN(C(=O)OCc2ccc(C(=O)O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 13, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid 4-methoxycarbonyl-benzyl ester (50 mg, 0.08 mmol) was heated with aqueous LiOH (19 mg, 0.8 mmol) in tetrahydrofuran (3 mL), water (3 mL), and methanol (1 mL) at room temperature for 18 h to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid 4-carboxy-benzyl ester as a white solid (Yield, 35 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]2[C@@H:13]([O:14][Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)[O:18][CH2:19]2)[C@@H:12]1[O:34][CH3:35]>C1COCC1.N1C=CC=CC=1.F.N1C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]([CH2:19][OH:18])[C@@H:13]([OH:14])[C@@H:12]1[O:34][CH3:35]
Reactant: CO[C@H]1[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@H]2O[C@H]1n1cnc2c(Cl)ncnc21
Agent: F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 6-chloro-9-[(6aR,8R,9S,9aR)-2,2,4,4-tetraisopropyl-9-methoxytetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-9H-purine (1.31 g, 2.41 mmol) in THF/pyridine (12 mL, 1:1) was added approximately 20 drops of hydrofluoric acid in pyridine. This solution was stirred at r.t. overnight. The reaction was diluted with EtOAc (10 mL) and quenched with saturated aq NaHCO3. The aq layer was extracted with EtOAc (3×40 mL) and the combined organics were dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash chromatography (0 to 10% MeOH/DCM) to afford the title compound (0.690 g, 74%).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].S(=O)(=O)(O)O.N[C:11]1[NH:15][N:14]=[C:13]([N+:16]([O-:18])=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20]>>[N+:1]([C:11]1[C:12]([N+:19]([O-:21])=[O:20])=[C:13]([N+:16]([O-:18])=[O:17])[NH:14][N:15]=1)([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: Nc1[nH]nc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1n[nH]c([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 20 °C

Procedure:
650 mg of sodium nitrite are added rapidly at 0-10° C. to a 20% solution of sulfuric acid (5 mL) containing 145 mg of 5-amino-3,4-dinitropyrazole. The mixture is left to react at this temperature for 1 hour and then the cold mixture is poured into 40 mL of 10% strength aqueous sodium nitrite which is maintained at 20° C. The mixture is subsequently heated at 50-60° C. for 30 minutes until the effervescence disappears completely. The excess sodium nitrite is then neutralized by addition of concentrated sulfuric acid. The reaction mixture is extracted 3 times with ethyl acetate. The organic phases are combined, washed with a brine, dried over magnesium sulfate, filtered and then concentrated. 3,4,5-Trinitropyrazole is obtained in the form of an orange gum with a crude yield of 80%. The NMR and IR analyses are in accordance with those obtained with the product of Example 3.
Reaction SMILES: [CH3:1][S:2]([CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[CH2:9][NH:10][CH3:11])=[O:3].Cl[C:16]1[NH:17][C:18]2[C:23]([C:24](=[O:26])[N:25]=1)=[C:22]([CH3:27])[C:21]([O:28][CH3:29])=[C:20]([O:30][CH3:31])[CH:19]=2.CCN(CC)CC.O>CS(C)=O>[CH3:1][S:2]([CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[CH2:9][N:10]([CH3:11])[C:16]1[NH:17][C:18]2[C:23]([C:24](=[O:26])[N:25]=1)=[C:22]([CH3:27])[C:21]([O:28][CH3:29])=[C:20]([O:30][CH3:31])[CH:19]=2)=[O:3]
Reactant: COc1cc2[nH]c(Cl)nc(=O)c2c(C)c1OC
Reactant: CNCc1cccc(OCS(C)=O)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cc2[nH]c(N(C)Cc3cccc(OCS(C)=O)c3)nc(=O)c2c(C)c1OC
Temperature: 120 °C

Procedure:
Compound from step 4 (213 mg, 1.00 mmol) and 2-chloro-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one (254 mg, 1.00 mmol) were dissolved in dry DMSO. Et3N (0.14 mL, 1.00 mmol) was added, and the mixture was heated to 120° C. overnight. Upon cooling, the mixture was poured into water and extracted with diethyl ether. The ethereal extracts were dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from MeOH to give 54 mg (12.53%) of the above Example F-2 as a white crystalline powder. mp 191.0–193.5° C.; 1H NMR (DMSO-d6, 2.49) δ 2.59 (s, 3 H), 2.60 (s, 3 H), 3.03 (s, 3 H), 3.62 (s, 3 H), 3.84 (s, 3 H), 4.79 (s, 2 H), 5.02 (d, 1 H, J=10.6), 5.22 (d, 1 H, J=10.6), 6.64 (s, 1 H), 6.90 (d, 1 H, J=7.6), 7.01 (m, 2 H), 7.30 (t, 1 H, J=7.9); 13C NMR (DMSO-d6, 39.50) δ 13.90, 34.66, 35.59, 51.90, 55.93, 60.23, 84.92, 104.81, 108.46, 114.18, 115.02, 121.22, 130.13, 131.94, 140.10, 142.90, 150.63, 150.97, 157.71, 157.97, 163.67; MS (ES+) m/z 432 (M+H); Anal. (C21H25N3O5S)C: calcd, 58.45; found, 58.32; H: calcd, 5.84; found, 5.74; N: calcd, 9.74; found, 9.77.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[C:4]([N+:14]([O-])=O)[CH:3]=1>C(O)C.N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[C:4]([NH2:14])[CH:3]=1
Reactant: COCCCOc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: COCCCOc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Stannous chloride (1.04 g, 5.49 mmol) was added to a solution of 4-chloro-1-(3-methoxy-propoxy)-2-nitro-benzene (0.448 g, 1.82 mmol) in a mixture of ethanol and ethyl acetate (1/1, 20 mL) and the resulting mixture was stirred at room temperature overnight. More stannous chloride (0.76 g, 4 mmol) was added and the reaction mixture was stirred for 1 day. The resulting mixture was partitioned between an aqueous solution of sodium bicarbonate (5%) and ethyl acetate, the aqueous solution was separated and extracted twice with ethyl acetate, the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The yellow oily residue was purified by flash chromatography (hexane/EtOAc, 80/20 to 60/40) to give 0.29 g (74% yield) of 5-chloro-2-(3-methoxy-propoxy)-phenylamine as a yellow oil.
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)[CH3:3].S(Cl)([Cl:17])=O>O1CCCC1>[ClH:17].[Cl:17][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc2c(c1)CCC(=O)N2
Solvent: C1CCOC1
Product: CC(Cl)c1ccc2c(c1)CCC(=O)N2
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a stirred mixture of 2 parts of intermediate 21, namely 3,4-dihydro-6-(1-hydroxyethyl)-2(1H)-quinolinone in 8.9 parts of tetrahydrofuran were added 1.62 parts of thionyl chloride. Stirring at room temperature was continued overnight. The reaction mixture was evaporated and the residue was co-evaporated with methylbenzene, yielding 2.3 parts (93.4%) of 6-(1-chloroethyl)-3,4-dihydro-2(1H)-quinolinone hydrochloride (interm. 36).
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)C(=O)C(=CC1CCCCC1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(O)C(=CC1CCCCC1)n1cncn1
Yield: 55.1 %

Procedure:
26 g (0.1 mol) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one(prepared as described in Example II-1) were taken up in 200 methanol, and 4.5 g of sodium borohydride were added in portions to the solution, while stirring and cooling. After the reaction had ended, the reaction mixture was adjusted to pH 6 and was concentrated. The residue was taken up in 200 ml of methylene chloride, and the solution was washed with saturated sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. The residue was recrystallized from petroleum ether. 14.5 g (55% of theory) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-ol of melting point 131° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH2:22][OH:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+].O>CN(C)C=O>[CH2:24]([O:23][CH2:22][C:11]1[C:12]([CH3:21])=[N:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]=1[S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1COCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
A solution containing 115 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-methanol, 54 mg of benzyl bromide and 38 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 100° C. for 2 hours. Water (10 ml) was added and the mixture was extracted three times with 8 ml of dichloromethane. Combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified twice by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40–60° C.) (1:4) then dichloromethane for the elution to give 35 mg of 4-benzyloxymethyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole as a colourless gum. Mass spectrum (ES) m/z 455 [M+H]+, 496 [M+H+CH3CN]+. 1H NMR (DMSO-dr) 2.36 (s, 3H), 4.47 (s, 2H), 4.49 (s, 2H), 6.96 (d, 2H), 7.24–7.47 (m, 11H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C:4]1([CH3:17])[CH3:16].[ClH:18].O1CCOCC1>CCOCC>[Cl-:18].[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][NH2+:6][CH2:5][C:4]1([CH3:17])[CH3:16]
Reactant: CO[C@H]1CCN(C(=O)OC(C)(C)C)CC1(C)C
Reactant: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CO[C@H]1CC[NH2+]CC1(C)C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To neat (S)-tert-butyl 4-methoxy-3,3-dimethylpiperidine-1-carboxylate (5.87 g, 24.1 mmol) was added 4.0 M HCl in dioxane (24.1 mL, 96.0 mmol), and the reaction mixture was stirred at room temperature for 16 h. Then, the reaction mixture was diluted with heptanes (60 mL) and Et2O (10 mL) and stirred at room temperature until a white solid crashed out. The heterogeneous mixture was then filtered and the white solid was collected to afford (S)-4-methoxy-3,3-dimethylpiperidin-1-ium chloride. 1H NMR (400 MHz, CDCl3) δ ppm 9.58 (br. s., 1 H), 9.23 (br. s., 1 H), 3.34 (s, 3 H), 3.09-3.24 (m, 2 H), 3.05 (t, J=10.0 Hz, 1 H), 2.97 (dd, J=5.4, 2.4 Hz, 1 H), 2.76 (d, J=13.1 Hz, 1 H), 2.04-2.17 (m, 1 H), 1.84-1.96 (m, 1 H), 1.19 (s, 3 H), 1.05 (s, 3 H).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:18][C:19]1[C:20]2[CH2:28][N:27]([C:29]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:30]=3[C:31]#[N:32])[CH2:26][CH2:25][C:21]=2[N:22]=[CH:23][N:24]=1)[C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.CCOC(C)=O>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:29]([N:27]2[CH2:26][CH2:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([NH:18][C@@H:10]([C:11]4[CH:16]=[N:15][C:14]([CH3:17])=[N:13][CH:12]=4)[CH2:9][OH:8])[C:20]=3[CH2:28]2)=[C:30]([CH:33]=1)[C:31]#[N:32]
Reactant: Cc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)Nc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ncc([C@@H](CO)Nc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-(4-(2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-chlorobenzonitrile (60 mg, 0.11 mmol) in THF (10 mL) was added 1M TBAF in THF (5 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then treated with water and EtOAc. The organic layer was washed with aq. NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was washed by ethyl ether and water (to completely remove TBAF) and dried to yield the final product as a light colored solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:19](=[O:20])[N:18]2[C:12]([C:13]([CH3:22])([CH3:21])[O:14][CH2:15][CH2:16][CH2:17]2)=[N:11][C:10]=1[C:23](O)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:57][CH2:58][C:59]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:60]=1[C:61]([NH:63][CH3:64])=[O:62].CN(C1C=CC=CN=1)C>CN(C)C=O>[F:69][C:66]1[CH:67]=[CH:68][C:59]([CH2:58][NH:57][C:23]([C:10]2[N:11]=[C:12]3[N:18]([C:19](=[O:20])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:22])=[O:24])=[C:60]([C:61](=[O:62])[NH:63][CH3:64])[CH:65]=1
Reactant: CNC(=O)c1cc(F)ccc1CN
Reactant: CC1(C)OCCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCOC2(C)C
Reaction time: 0.17 h

Procedure:
A solution of intermediate 35, 3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylic acid in anhydrous dimethylformamide (4 mL) was treated with HATU (0.278 g, 0.70 mmol) and stirred for 10 minutes. The reaction mixture was treated with 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetic acid salt (0.24 g, 0.8 mmol), followed by dimethylaminopyridine (0.121 g, 0.97 mmol), then stirred for 4 hours at 60° C. Following this, the solvent was removed in vacuo and the remaining residue dissolved in ethyl acetate (15 mL) and washed with 1.0 N HCl (15 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO2), eluting with ethyl acetate. Fractions containing the product were pooled, concentrated to dryness and triturated with ether to provide 0.366 g of the title compound as a white glassy solid. 1H NMR (500 MHz, d6-acetone) δ ppm: 8.71-8.82 (1H, m), 7.84-7.95 (1H, br), 7.47-7.62 (4H, m), 7.27-7.40 (5H, m), 7.20 (1H, dt, J=8.5, 2.7 Hz), 5.15-5.21 (2H, br, s), 4.48-4.60 (4H, m), 2.96 (2H, s), 2.94 (2H, s), 1.62-1.64 (6H, s).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH:14]([NH2:20])[CH2:13]2>C(N(CC)CC)C.ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH:14]([NH:20][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH2:13]2
Reactant: CCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(N)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1Cc2cc(OC)c(OC)cc21
Reaction time: 8 h
Yield: 80 %

Procedure:
1.5 mL of ethyl chloroformate are poured into a suspension of 3.4 g of the compound obtained in Step 1 in 4.5 mL of triethylamine and 50 mL of dichloromethane and left overnight, whilst stiffing at ambient temperature; washing with water and with 1N hydrochloric acid is then carried out. Drying is carried out and the solvent is evaporated off to dryness. 3.2 g of an oil corresponding to the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:21]1C=[N:23][C:24](Cl)=[CH:25][C:26]=1[CH3:27].[CH3:29][S-].[Na+].C[S:33]([CH3:35])=O>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:21]1[C:35]([SH:33])=[N:23][C:24]([CH3:29])=[CH:25][C:26]=1[CH3:27]
Reactant: CS(C)=O
Reactant: COc1cccc(C)c1N(C)C(=O)c1ccc(Cl)c(-c2cnc(Cl)cc2C)c1
Reactant: C[S-]
Agent: [Na+]
Product: COc1cccc(C)c1N(C)C(=O)c1ccc(Cl)c(-c2c(C)cc(C)nc2S)c1
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide 2-31 (20.0 mg, 0.048 mmol) and sodium thiomethoxide (3.3 mg, 0.048 mmol) in DMSO (1 mL) was heated at 80° C. for 1 hr. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and purified by HPLC yielding 4-chloro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-3-(4-methyl-6-methyl-sulfanylpyridin-3-yl)-benzamide (4.3 mg). MS (M+H)+: 426.9; tR=7.92 min. (method 2).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:14])([CH3:13])[CH3:12])(=[O:9])=[O:8].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[OH:14][C:11]([CH3:13])([CH3:12])[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[S:7]([NH2:6])(=[O:8])=[O:9]
Reactant: COc1ccc(CNS(=O)(=O)C(c2ccccc2)C(C)(C)O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(O)C(c1ccccc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A solution of 2.67 g of N-(2,4-dimethoxybenzyl)-2-hydroxy-2-methyl-1-phenylpropane-1-sulfonamide in 20 ml of dichloromethane was admixed with 3.74 ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The starting solution was coevaporated twice with 100 ml of toluene and the crude product was purified using by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (0.90 g) with a molecular weight of 229.3 g/mol (C10H15NO3S).