Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][C:8]1([CH2:12][S:13][CH2:14][C:15]2([CH3:19])[CH2:18][O:17][CH2:16]2)[CH2:11][O:10][CH2:9]1.[OH2:20]>CO>[S:13]([CH2:12][C:8]1([CH3:7])[CH2:11][O:10][CH2:9]1)([CH2:14][C:15]1([CH3:19])[CH2:16][O:17][CH2:18]1)(=[O:1])=[O:20]
Reactant: O=S([O-])OO
Reactant: CC1(CSCC2(C)COC2)COC1
Reactant: O
Agent: [K+]
Solvent: CO
Product: CC1(CS(=O)(=O)CC2(C)COC2)COC1
Temperature: 10 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A suspension of oxone (650 mg, 1.06 mmol) in water (2.0 mL) was cooled to 10° C. and treated (dropwise) with a solution of 6 (108 mg, 0.533 mmol) in MeOH (2.0 mL). The solution was warmed to rt and stirred for 1 h. MeOH was removed in vacuo, and the aqueous layer was diluted with water (5 mL) and extracted with CH2C12 (4×10 mL). The combined organic layers were washed with brine (5 mL), dried (MgSO4), and concentrated in vacuo to afford the sulfone (120 mg, 96%) as a white solid: Mp 93.4-95.1° C.; IR (ATR) 2949, 2867, 1456, 1301, 1277, 967 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.68 (d, J=6.4 Hz, 4H), 4.46 (d, J=6.4 Hz, 4H), 3.43 (s, 4H), 1.69 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 82.2, 62.6, 37.9, 23.3; HRMS (APCI) m/z calc for C10H19O4S (M+H) 235.1004. found 235.1032.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH:8]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:4][CH:3]=1.[C:31](C1NC=CN=1)(C1NC=CN=1)=[O:32].C(N(CC)CC)C.Cl.[C:51]([C:53]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)#[N:52]>ClCCl.CN(C1C=CN=CC=1)C.CN1CCCC1=O>[C:51]([C:53]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:54][CH2:55][N:56]([C:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH2:8])=[CH:29][CH:30]=2)=[O:32])[CH2:57][CH2:58]1)#[N:52]
Reactant: Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC1(c2ccccc2)CCN(C(=O)Nc2ccc(C[C@H](N)C(=O)O)cc2)CC1

Procedure:
4-Amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine on Wang resin (300 mg, 0.228 mmol) obtained from Example 62 was placed in a vessel fitted with a glass frit and was washed with dichloromethane (2×10 mL), methanol (2×10 mL) and dichloromethane (2×10 mL). To the resin was added carbonyl diimidazole (0.22 g, 1.4 mmol) and triethylamine (0.38 mL, 2.7 mmol) in 3 mL of dichloromethane. The mixture was agitated over night. The mixture was then filtered and washed with dichloromethane (3×5 mL). To the resin was added 4-cyano-4-phenylpiperidine hydrochloride (0.25 g, 1.14 mmol) and DMAP (0.14 g, 1.14 mmol) in 3 mL of N-methylpyrrolidinone. The resulting mixture was agitated for 3 hours. The reaction mixture was then filtered and washed with dichloromethane (2×10 mL). methanol (2×10 mL), dimethylformamide (2×10 mL) and methanol (2×10 mL). Cleavage of the Fmoc group was effected with 25% piperidine in N-methylpyrrolidinone (2×15 min to give 4-[[(4-cyano-4-phenyl-1-piperidinyl)carbonyl]amino]-L-phenylalanine on Wang resin.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:18]2[CH:17]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.CC(O)(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][N:28]([CH2:3][CH:2]([OH:1])[CH2:4][N:5]2[C:18]3[CH:17]=[C:16]([C:19]([F:21])([F:20])[F:22])[CH:15]=[CH:14][C:13]=3[S:12][C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:29][CH2:30]1
Reactant: FC(F)(F)c1ccc2c(c1)N(CC1CO1)c1ccccc1S2
Reactant: C1COCCN1
Solvent: CC(C)(C)O
Product: OC(CN1CCOCC1)CN1c2ccccc2Sc2ccc(C(F)(F)F)cc21

Procedure:
Utilizing the procedure outline in Example 1, Step 2, (±)-10-(oxiran-2-ylmethyl)-2-(trifluoromethyl)-10H-phenothiazine and 2-methyl-2-propanol (127 mg, 0.39 mmol) was reacted with morpholine (41 μL, 0.48 mmol) to afford the title compound. LCMS m/z 411 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.C(O)C(O)C.Cl[S:17]([C:20]1[N:28]=[C:27]2[N:22]([C:23]([O:30][CH3:31])=[N:24][CH:25]=[C:26]2[F:29])[N:21]=1)(=[O:19])=[O:18]>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH:6][S:17]([C:20]2[N:28]=[C:27]3[N:22]([C:23]([O:30][CH3:31])=[N:24][CH:25]=[C:26]3[F:29])[N:21]=2)(=[O:18])=[O:19])=[C:4]([F:10])[CH:3]=1
Reactant: COc1ncc(F)c2nc(S(=O)(=O)Cl)nn12
Reactant: Nc1c(F)cc(Cl)cc1F
Solvent: ClCCl
Solvent: CC(O)CO
Product: COc1ncc(F)c2nc(S(=O)(=O)Nc3c(F)cc(Cl)cc3F)nn12
Temperature: 35 °C

Procedure:
A mixture of 24.0 g (147 mmol) of 4-chloro-2,6-difluoroaniline and 22.9 g of 1,2-propanediol was placed in a round bottom flask and heated to 35° C. with stirring. A mixture of 14.5 g (49 mmol) of 88 percent purity 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine with 29.1 g of dichloromethane was prepared and was added in 1 mL shots over a 4 hour period. The resulting mixture was heated another 4 hours and was then stirred overnight at ambient temperature. It was then cooled to about 20° C. and filtered, collecting the solids present. The solids were slurried in 30 mL of a 1:1 mix of 2-propanol and water, collected by filtration, washed with 2×30 mL of 2-propanol, and air dried to obtain 14.8 g (75 percent of theory) of the title compound as a white powder of 98 percent purity melting at 203-204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.C(O)(=O)C.[O-:15][C:16]#[N:17].[K+]>O>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:17][C:16]1=[O:15]
Reactant: N#C[O-]
Reactant: COC(=O)c1sccc1N
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
To a mixture of methyl 3-amino-thiophenecarboxylate 1 (850 g, 5.41 mol, 1.0 equiv.), acetic acid (6 L) and water (5 L), a solution of potassium cyanate (KOCN, 1316 g, 16.22 mole, 3.0 equiv.) in water (3.2 L) was added slowly over a period of 1 hour. The resulting mixture was stirred at the ambient temperature for 20 hour, filtered and rinsed with water (4 L). The cake was charged to a suitably sized reactor and 2 M aqueous sodium hydroxide solution (14 L) was added. The slurry was stirred for 2 hours and LCMS confirmed the formation of the desired product. The mixture was cooled to 10° C. and 3 M aqueous hydrochloric acid (˜11 L) was added until pH=5.0-6.0 (by pH paper). The slurry was filtered, rinsed with water (6 L), dried in vacuum oven at 50° C. for 24 hours to afford thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 2 as an off-white solid (834 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 6.90 (d, J=5.2 Hz, 1H), 8.10 (d, J=5.2 Hz, 1H), 5.40-5.55 (br s, 2H). LCMS (ESI pos) m/e 169 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[NH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13]1>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13]2)=[S:10])=[CH:4][CH:3]=1
Reactant: Nn1cnc2ccccc2c1=O
Reactant: S=C=Nc1ccc(Br)cc1
Solvent: ClCCCl
Product: O=c1c2ccccc2ncn1NC(=S)Nc1ccc(Br)cc1

Procedure:
4-Bromophenyl isothiocyanate (2.51 g, 11.72 mmol) is added to a mixture of 3-amino-4(3H)quinazolinone (1.72 g, 10.66 mmol) in 1,2-dichloroethane at reflux under a nitrogen atmosphere. The reaction mixture is heated at reflux for 2 days, cooled, washed with ether and filtered. The filter cake is dried to give the title product as a white solid, 2.44 g, mp 189°-190° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[K])(C)(C)C.O>CN1C(=O)CCC1>[CH2:11]([O:18][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: OCc1ccccc1
Agent: CC(C)(C)O[K]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1ccnc(OCc2ccccc2)c1
Temperature: 125 °C
Reaction time: 6 h
Yield: 71.3 %

Procedure:
2-Chloro isonicotinic acid (9.45 g) and benzyl alcohol (12.977 g) were dissolved in NMP (180 mL), and treated with tBuOK (20.2 g) between 10-25° C. The reaction mixture was then stirred at 125° C. (Bath-temperature) for 6 h, cooled down to r.t., poured into water (1500 ml) and extracted twice with water. The combined aqueous phases were treated with concentrated aqueous HCl until pH 3 (16 ml). After 10 min the solid was filtered, washed with water and dried under high vacuum, to give the title compound as an off-white solid (9.8 g). MS (m/e)=228.1 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[CH:19]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)([CH3:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[ClH:13].[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[CH:15][CH:16]=[C:17]([OH:18])[C:2]=2[NH:1][CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24]2)=[N:8][CH:9]=1
Reactant: CC(C)N1CCC(C=O)CC1
Reactant: Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N1CCC(CNc2c(O)cccc2C(=O)Nc2ccc(Cl)cn2)CC1
Product: Cl
Temperature: 70 °C
Reaction time: 15 h
Yield: 122.4 %

Procedure:
2-Amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (100 mg) and 80 mg of 1-isopropylpiperidine-4-carbaldehyde were suspended in 5 ml of toluene, then 10 mg of p-toluenesulfonic acid hydrate were added thereto and the mixture was heated to reflux for 2 hours together with removal of water by an azeotropic operation. After the solvent was evaporated in vacuo, 7 ml of acetic acid and 88 mg of a boran-trimethylamine complex were added to the resulting residue and the mixture was stirred at 70° C. for 15 hours. The solvent was evaporated in vacuo, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and the resulting residue was purified by means of a silica gel column chromatography. After addition of 1N hydrochloric acid and water to the resulting N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[(1-isopropyl-4-piperidyl) methyl]amino}benzamide and the mixture was freeze-dried to give 102 mg of N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[(1-isopropyl-4-piperidyl)methyl]amino}benzamide hydrochloride.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@H:4]1[CH3:50].[C:51](OC(=O)C)(=[O:53])[CH3:52].C(OCC)(=[O:60])C>>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[O:44][C:51]([CH3:52])=[O:53])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:60])[CH3:50]
Reactant: CCOC(C)=O
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@H]1C
Reactant: CC(=O)OC(C)=O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1.0 L one neck round bottom flask were placed 50 g of erythromycin B (69.64 m mole), 500 mL ethyl acetate and 16 mL acetic anhydride (17.3 g, 169.6 m mole). The solution was stirred at room temperature overnight. Copious amounts of white solids were observed. This mixture was filtered to give 26.2 g solid. The filtrate was washed with 300 mL 5% sodium bicarbonate twice, and the organic layer was dried with magnesium sulfate. The solvent was removed by vacuum distillation to give a second crop of desired product (22.3 g). The product was identified by mass spectroscopy and NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)(=O)C>C1COCC1.[Zn]>[NH2:13][C:10]1[CH:11]=[CH:12][C:2]([CH3:1])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1C
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(N)ccc1C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of ethyl 2-methyl-5-nitrobenzoate 101 and acetic acid (516 mmol, 29.6 mL) (25.8 mmol, 5.4 g) in THF (129 mL) at 0° C. was added zinc (516 mmol, 33.8 g) and stirred for 1 h. The reaction was filtered, neutralized with 2N NaOH solution and extracted with ethyl acetate (2×). Organic layers were washed with water, brine, dried and concentrated under reduced pressure to give ethyl 5-amino-2-methylbenzoate 102 (4.6 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[CH3:26][C:27]([CH2:29][CH3:30])=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:27]([CH2:29][CH3:30])[CH3:26])[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: CCC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(C)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(C)cn2)CC1
Temperature: 50 °C
Reaction time: 96 h
Yield: 50.1 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with methylethyl ketone (1.12 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol afforded 0.26 g (50%) of the title compound as a tan solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[S:7]1[C:11]([CH2:12][CH2:13][NH2:14])=[CH:10][C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2>C(Cl)(Cl)Cl.C(N(CC)CC)C>[S:7]1[C:11]([CH2:12][CH2:13][NH:14][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[CH:10][C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2
Reactant: CCOC(=O)Cl
Reactant: NCCc1cc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCCc1cc2ccccc2s1
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (0.18 ml) was added dropwise to a stirred, ice-cooled solution of benzo[b]thiophene-2-ethanamine (300 mg) in a mixture of chloroform (8 ml) and triethylamine (0.28 ml) under nitrogen and stirring was continued at 0° for 30 min. The solution was evaporated, the residue was treated with water (10 ml), extracted with dichloromethane (3×10 ml) and the combined, dried organic extracts were evaporated to give an oily solid. This was purified by FCC eluting with System B (1:2) to give the title compound (313 mg), m.p. 65°-66°.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([CH:12]([C:14]([CH:16]([Cl:28])[C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19])=[O:15])[Cl:13])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:29](=[O:32])([O-])[O-].[K+].[K+].[CH:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(Cl)Cl.O>[CH:35]1([C:41]([NH:19][C@H:18]([C:17]([CH:16]([C:14]([CH:12]([Cl:13])[C:10](=[O:11])[C@H:2]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:1][C:29]([CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:32])=[O:15])[Cl:28])=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N[C@@H](Cc1ccccc1)C(=O)C(Cl)C(=O)C(Cl)C(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)C(Cl)C(=O)C(Cl)C(=O)[C@H](Cc1ccccc1)NC(=O)C1CCCCC1)C1CCCCC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 162.5 %

Procedure:
A cooled (−10° C.) mixture containing L-phenylalanylchloromethylketone (3.2 mmole) in CH2Cl2 (30 ml) and potassium carbonate (10 mmole) in water (10 ml) was treated with cyclohexanecarbonylchloride (3.2 mmole). The resulting mixture was stirred for two hours at ambient temperature. The organic layer was separated, washed with water (3×20 ml) and dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave the titled compound as a cream colored solid (2.6 mmole, 81%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[CH3:38][NH:39][CH3:40]>>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24][N:39]([CH3:40])[CH3:38])[C:12]2=[O:26])[CH2:27][CH2:28]1)=[O:7]
Reactant: CNC
Reactant: Cc1ccccc1N1CN(CCO)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1CN(CCN(C)C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=557.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and dimethylamine.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:13])[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[CH3:20]B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:8]1[C:7]([F:13])=[C:6]2[C:11]([C:2]([CH3:20])=[CH:3][C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: CB(O)O
Reactant: Fc1c(Cl)ccc2c(Br)cc(-c3ccccc3)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2)nc2c(F)c(Cl)ccc12
Temperature: 108 °C

Procedure:
4-Bromo-7-chloro-8-fluoro-2-phenylquinoline (1.1 g, 03.3 mmol), methane boronic acid (196 mg, 3.27 mmol), potassium carbonate (1.4 g, 9.8 mmol) and 1,4-dioxane (4 mL) were combined and stirred in a 10 mL R.B. flask. The flask was subjected to 3 vacuum-argon cycles. Tetrakis(triphenylphosphine)palladium(0) (380 mg, 0.33 mmol) was added, and the reaction was again subjected to 3 vacuum argon-cycles. The reaction was heated at 108° C. (external temperature) for 27 h, at which point the reaction was allowed to cool, and was diluted with ethyl acetate (30 mL), and water (30 mL). The layers were separated, and the aqueous layer extracted with ethyl acetate (30 mL). The organics were combined, dried over sodium carbonate, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexanes:methylene chloride 2:1. This afforded the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 2.75 (s, 3H), 7.47-7.55 (m, 4H), 7.69-7.72 (dd, 1H, J=8.9 & 1.6 Hz), 7.77 (s, 1H), 8.18-8.21 (m, 2H); MS (APCI+): 272.07 (100) [MH+], 274.03 (30) [(M+2)H+]; HPLC tR=3.80 min (OpenLynx, nonpolar—5 min).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[NH:24][C:25]2[C:26]3[C:33]([CH3:34])=[C:32]([C:35]([NH2:37])=[O:36])[S:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([NH:24][C:25]2[C:26]3[C:33]([CH3:34])=[C:32]([C:35]([NH2:37])=[O:36])[S:31][C:27]=3[N:28]=[CH:29][N:30]=2)=[C:17]([O:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([NH:9][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:11][CH2:12]2)[CH:22]=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](N)CC3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](NC4CCN(C)CC4)CC3)c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
0.019 g 1-methyl-4-piperidone in 1.5 ml MeOH followed by 1 drop acetic acid were added to a mixture of 0.070 g 4-(2-(trans-4-aminocyclohexyloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxamide (cpd.15.2) in 2 ml methanol. Sodium cyanoborohydride was added when the mixture was stirred at rt for 40 min. After stirring at 50° C. for 3 h further 0.010 g 1-methyl-4-piperidone and 0.010 g sodium cyanoborohydride were added and heating was continued overnight.
Reaction SMILES: CN(C)C=O.[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].CS[C:13]1[S:17][CH:16]=[CH:15][S+:14]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CC(C)=O>[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].[S:14]1[CH:15]=[CH:16][S:17][C:13]1=[N+:19]([CH3:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CSc1scc[s+]1
Reactant: CNc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[N+](c1ccccc1)=c1sccs1
Temperature: 25 °C

Procedure:
To 2 ml of dimethylformamide, 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was suspended, and 1.1 ml of N-methylaniline was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and then after an addition of 30 ml of ethyl acetate, the precipitated crystals were collected by filtration. The product was recrystallized from acetone, whereby 1.7 g (yield: 69%) of N-(1,3-dithiol-2-ylidene)-N-methyl-N-phenylammonium perchlorate (Compound No. 8) was obtained as crystals having a melting point of 169° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:15]([CH2:16][CH2:17][Cl:18])[CH:14]=[N:13][C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].C1COCC1.CO>C1(C)C=CC=CC=1>[NH2:12][C:9]1[C:8]2[N:13]=[CH:14][N:15]([CH2:16][CH2:17][Cl:18])[C:7]=2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(N)c2ncn(CCCl)c12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncc(C(=O)O)c2c1ncn2CCCl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.5 %

Procedure:
To a mixture of 50 mg (0.19 mmol) of 4-amino-1-[2-chloro-ethyl]-1H-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester (example 10 step B) and 1.1 ml of a 2M aqueous solution of NaOH were added 0.3 ml of THF and 0.8 ml of MeOH. The mixture was stirred for 2.5 hours at room temperature. MeOH and THF were evaporated under reduced pressure and the pH of the remaining mixture was adjusted to pH=2 with 2N aqueous HCl. The product precipitated and was isolated by filtration. Toluene was added to the product and the solvent was evaporated. This process was repeated three times. Finally 24 mg (53%) of the desired product were isolated as a light grey solid.