Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].C(O[CH:17](N(C)C)[N:18]([CH3:20])[CH3:19])(C)(C)C>>[CH3:17][N:18]([CH3:20])[CH:19]=[C:7]1[CH2:6][O:5][CH2:4][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:2]1=[O:1]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COC(=O)C1COCCC1=O
Product: COC(=O)C1COCC(=CN(C)C)C1=O

Procedure:
Methyl 4-oxo-tetrahydro-pyran-3-carboxylate (74 mg, 0.47 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (101 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 214.4 [(M+H)+].
Reaction SMILES: S1C=CN=C1C1SC2C(=NC=CC=2OC2C=CC(NC(NC(=O)CC3C=CC=CC=3)=S)=CC=2F)C=1.CCCCCCCCCCCCN.[F:49][C:50]1[CH:51]=[C:52]([NH:71]C(NC(=O)CC2C=CC=CC=2)=S)[CH:53]=[CH:54][C:55]=1[O:56][C:57]1[C:58]2[S:65][C:64]([C:66]3[S:67][CH:68]=[CH:69][N:70]=3)=[CH:63][C:59]=2[N:60]=[CH:61][N:62]=1>>[F:49][C:50]1[CH:51]=[C:52]([NH2:71])[CH:53]=[CH:54][C:55]=1[O:56][C:57]1[C:58]2[S:65][C:64]([C:66]3[S:67][CH:68]=[CH:69][N:70]=3)=[CH:63][C:59]=2[N:60]=[CH:61][N:62]=1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3cc(-c4nccs4)sc23)c(F)c1
Agent: CCCCCCCCCCCCN
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: Nc1ccc(Oc2ncnc3cc(-c4nccs4)sc23)c(F)c1
Yield: 7 %

Procedure:
Starting from the nitro compound 150, following the procedure described above for the synthesis of compound 13a (via the intermediate amine 12, scheme 2, example 12), title compound 152a was obtained [via intermediate 3-fluoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)benzenamine (151)] in 7% yield. Characterization of 152a is provided in the Table 14.
Reaction SMILES: I[CH3:2].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:9](=[C:14]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[C:28]([F:31])([F:30])[F:29])[O:15][N:16]=3)[CH2:10][NH:11][C:12]=2[CH:13]=1.[H-].[Na+]>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:9](=[C:14]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[C:28]([F:31])([F:29])[F:30])[O:15][N:16]=3)[CH2:10][N:11]([CH3:2])[C:12]=2[CH:13]=1
Reactant: CI
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1onc2c1CNc1cc(Br)ccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2c(noc2-c2onc(-c3ccccc3)c2C(F)(F)F)-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
Iodomethane (0.020 mL, 0.325 mmol) was slowly added to a stirred mixture of 7-bromo-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydroisoxazolo[4,3-c]quinoline (Preparation 77D, 0.050 g, 0.108 mmol) and sodium hydride (2.60 mg, 0.108 mmol) in THF (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 1 N aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (3×25 mL). The ethyl acetate extract was dried over sodium sulfate and concentrated to give 7-bromo-5-methyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydroisoxazolo[4,3-c]quinoline (0.041 g, 0.084 mmol, 78%) as an orange solid. The product had an HPLC ret. time=4.45 min. (condition B). LC/MS M+1 478.0.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]([NH:22][C:23]#[N:24])=[N:18][CH2:19][CH2:20][NH2:21])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>CO.CCOCC>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]([NH:22][C:23]#[N:24])=[N:18][CH2:19][CH2:20][NH:21][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[Cl:25])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N#CNC(=NCCN)NC1CCCC(c2csc(NC(=N)N)n2)C1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOCC
Solvent: CO
Product: N#CNC(=NCCNC(=O)c1ccccc1Cl)NC1CCCC(c2csc(NC(=N)N)n2)C1
Reaction time: 16 h

Procedure:
To a solution of 2-guanidino-4-{3-[3-cyano-2-(2-aminoethyl)guanidino]cyclohexyl}thiazole (0.5 g.) in methanol (30 ml.) was added o-chlorobenzoyl chloride (0.4 g.) and the mixture allowed to stand at room temperature for 16 hours. The residue obtained by evaporation of the solvent was partitioned between ethyl acetate (100 ml.) and water (20 ml.) The organic layer was isolated, washed with water (20 ml), dried (magnesium sulphate) and evaporated. The residue was subjected to preparative thin layer chromatography on Merck 60 F-254 plates using chloroform/methanol/aqueous ammonia (s.g. 0.88) 80:20:0.1 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform 50:50 v/v (200 ml.) and the residue obtained on evaporation of the solvents was dissolved in methanol. To this solution was added an excess of maleic acid in ether followed by a further amount of ether until precipitation began. The white powder precipitate (0.2 g.) was washed with ether to give 2-guanidino-4-{ 3-[3-cyano-2-(2-(2-chlorobenzoylamino)ethyl)guanidino]cyclohexyl}thiazole hydrogen maleate, m.p. 158°-165° (decomp.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C)(C)C.Cl>CO>[CH:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCCCNC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: NCCCCNC(c1ccccc1)c1ccccc1

Procedure:
Batch size: 4.6 g (<11.3 mmol) N-[4-(benzhydryl-amino)-butyl]-carbamic acid tert-butyl ester and 5.2 ml (63 mmol) concentrated hydrochloric acid in 50 methanol.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH:33]([OH:35])[CH:32]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[N:38]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]1[CH2:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[N:38]=2)[CH2:31]1)=[O:29])([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2CN(C(=O)OC(C)(C)C)CC2O)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(CC2CN(C(=O)OC(C)(C)C)CC2=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a suspension of Dess-Martin periodinane (0.0014 mol) in 10 mL CH2Cl2 was added a solution of 3-(6-tert-butoxycarbonylamino-pyridin-2-ylmethyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester III-2 (0.001 mol) in 5 mL CH2Cl2 and the reaction mixture was stirred at room temperature for 18 h. 1 M Na2S2O3 (10 mL) was added to the reaction, and after stirring for 10 min, the reaction mixture was extracted with CH2Cl2 (10 mL×3). The combined organic layers were washed with 5% aqueous NaHCO3 (20 mL×3) and brine (20 mL×2). The organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes:EtOAc, 8:2) to give pure product (96%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1.C(Cl)Cl>CN(C)C1C=CN=CC=1.CO>[C:11]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10])(=[O:13])[CH3:12]
Reactant: C#CCN1CC[C@H](O)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: C#CCN1CC[C@H](OC(C)=O)C1=O
Reaction time: 0.33 h

Procedure:
A solution of 4.3 g of (S)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 10.6 ml of acetic anhydride, 0.6 ml of pyridine, 0.1 g of 4-(dimethylamino)pyridine and 85 ml of methylene chloride is stirred at room temperature for 18 hours. Twenty-five ml of methyl alcohol is added and the reaction stirred for 20 minutes. The mixture is washed with 1N hydrochloric acid and saturated sodium bicarbonate. The organic layer is dried, passed thorough a pad of hydrous magnesium silicate and concentrated in vacuo to give 4.9 g of the desired product as a pale yellow oil.
Reaction SMILES: C[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([C:13]([O:15]CC)=[O:14])[C:5]([C:8]([O:10]CC)=[O:9])=[N:6][CH:7]=1.C1(C2C=CN=C(C(OCC)=O)C=2C(OCC)=O)C=CC=CC=1>>[C:18]1([C:3]2[CH:2]=[CH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[C:4]=2[C:13]([OH:15])=[O:14])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ncc(C)c(-c2ccccc2)c1C(=O)OCC
Agent: CCOC(=O)c1nccc(-c2ccccc2)c1C(=O)OCC
Product: O=C(O)c1nccc(-c2ccccc2)c1C(=O)O

Procedure:
In place of diethyl 5-methyl-4-phenyl-2,3-pyridinedicarboxylate in Step 1 in Reference Example 33, diethyl 4-phenyl-2,3-pyridinedicarboxylate (see Japanese Patent Laid-Open No. 62-106081) was reacted and treated in the same manner as in Step 1 in Reference Example 33, to obtain 4-phenyl-2,3-pyridinedicarboxylic acid as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=1[CH:17]([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=1.C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=2)[C:11]=1[CH:17]([CH3:18])[CH3:19])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)c1c(O)cccc1CCNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1c(CCNC(=O)OC(C)(C)C)cccc1Oc1ccc(C#N)cn1
Yield: 74.8 %

Procedure:
Using a method similar to Example 221, Step 1, using [2-(3-hydroxy-2-isopropyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (4.02 g, 14.4 mmol), 6-chloronicotinonitrile (1.99 g, 14.4 mmol) and K2CO3 (2.98 g, 21.5 mmol) gives {2-[3-(5-cyano-pyridin-2-yloxy)-2-isopropyl-phenyl]-ethyl}-carbamic acid tert-butyl ester (4.11 g) as a yellow foam. 1HNMR (CDCl3): 8.50 (s, 1H), 7.92 (d, 1H), 7.17 (t, 1H), 7.06 (d, 1H), 7.01 (d, 1H), 6.86 (d, 1H), 4.63 (br. s, 1H), 3.34 (m, 2H), 3.27 (m, 1H), 2.91 (t, 2H), 1.44 (s, 9H), 1.24 (d, 6H).
Reaction SMILES: [N+:1]([C:4]1(C([O-])=O)[CH:13]=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5]1)([O-:3])=[O:2].[CH3:17][OH:18]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([CH2:17][OH:18])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)C1=CC=CC(C(=O)[O-])([N+](=O)[O-])C1
Reactant: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)cc([N+](=O)[O-])c1

Procedure:
To a solution of monomethyl 3-nitroisophthalate (396.0 g, 1.76 mol) in anhydrous THF (1000 ml) was added 2.0M BMS (borane methylsulfide complex) in THF (880 ml, 1.76 mol) dropwise over 1 hour. The resulting solution was heated to reflux for 12 hours, and MeOH (750 ml) was slowly added to quench the reaction. The solution was concentrated to give a yellow solid which was recrystalized from toluene (297.5 g, 80%). 1H NMR (CDCl3): 8.71-8.70 (m, 1H), 8.41-8.40 (m, 1H), 8.31-8.30 (m, 1H), 4.86 (s, 2H), 3.96 (s, 3H), 2.47 (s, 1H); MP=76.5°-77.5° C.; DCI-MS: [M+H]=212.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[C:27]([O-:30])(O)=O.[Na+]>Br>[Cl:1][C:2]1[C:3]([NH:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][C:27]=2[OH:30])=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Agent: Br
Agent: [Na+]
Product: Oc1ccccc1Nc1c(Cl)cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c12
Temperature: 110 °C
Yield: 58 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (2:9 mg, 7.4 μmol) was dissolved in 48% aqueous HBr (1 ml) and heated at 110° C. for 3 h. whereupon the mixture was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc (5 ml). The organic phase was washed with brine, dried (MgSO4) and evaporated to give a white powder (2.0 mg, 58%).
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)[CH3:2].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].C(NC)C>CN(C=O)C>[CH2:1]([N:3]([CH3:4])[C:9](=[O:10])[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: CCNC
Solvent: CN(C)C=O
Product: CCN(C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 40.7 %

Procedure:
Triethylamine (12.84 g, 127.11 mmol) and p-nitrophenyl chloroformate (63.56 mmol, 12.8 g) were added to a room temperature solution of N-ethylmethylamine (2.50 g, 42.37 mmol) in dry DMF (70 mL) under an argon atmosphere. After 2 h, the reaction mixture was quenched with water, diluted with EtOAc (200 mL), washed with water (2×100 mL), and brine (75 mL). All volatiles were removed under reduced pressure and the residue was purified by SiO2 column chromatography using 10% EtOAc/hexanes to afford compound 4-nitrophenyl ethyl(methyl)carbamate (5.8 g, 76%) as a yellow oil. TLC: 20% EtOAc/hexanes, Rf≈0.50; 1H NMR (CDCl3, 300 MHz) δ 8.18-8.21 (m, 2H), 7.25-7.29 (m, 2H), 3.37-3.46 (m, 2H), 3.05 and 2.97 (s, 3H for two rotamers in 60/40 ratio), 1.17-1.22 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:4]1[C:3](=[O:10])[C:2]([Br:1])=[CH:7][N:6]=[C:5]1[S:8][CH3:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: CSc1ncc(Br)c(=O)[nH]1
Solvent: C1CCOC1
Product: CSc1ncc(Br)c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
5-bromo-2-(methylthio)pyrimidin-4(3H)-one (3.63 g, 16.4 mmol) was suspended in THF (80 ml) and CaH2 powder (1.29, 32.3 mmol) and benzyl bromide (2.6 ml, 22 mmol) were added. The reaction flask was fitted with a reflux condenser and placed in a preheated oil bath (65 C-70 C) and stirred overnight. After 15.5 hours, more benzyl bromide (0.7 ml, 6 mmol) was added, and the temperature of the oil bath was raised to 87 C to achieve reflux. After 19 more hours, the reaction was cooled to 0 C and quenched cautiously with ice water first, and then with water (40 ml). The reaction was warmed to room temperature and stirred as more water (40 ml) and then brine (30 ml) were added. The reaction was extracted with a DCM/MeOH mixture, and the organic extractions were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was filtered through silica gel (˜3 inches, DCM) to afford the desired 3-benzyl-5-bromo-2-(methylthio)pyrimidin-4(3H)-one (642 mg, 2.06 mmol, 90% purity, 11% yield). MS (ESI pos. ion) m/z: 311 (MH+), 313 (MH+). Calc'd exact mass for C12H11BrN2OS: 310, 312. 1HNMR (400 MHz, CDCl3): 8.09 (s, 1H), 7.42-7.29 (m, 5H), 5.34 (s, 2H), 2.54 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([N:1]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(N2C(=O)CCC2=O)cn1
Temperature: 25 °C

Procedure:
A mixture of 5-amino-2-methoxypyridine (1.24 g, 10.0 mmol) and succinic anhydride (1.00 g, 10.0 mmol) was heated with a heat gun for 10 minutes. After cooling to room temperature the product was purified by flash column chromatography (SiO2, ethyl acetate:acetone 25:75). Evaporation of the solvent yielded the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:31]([CH3:45])[CH2:32][CH2:33][N:34]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:34][CH2:33][CH2:32][CH:31]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[CH3:45]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(N(Cc2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(Cc2ccccc2)C2CCN(C(C)CCN)CC2)cc1

Procedure:
Using general procedure C with the above carbamate (303 mg, 0.765 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (320 mg, 1.47 mmol) and then using general procedure D gave [1-(3-amino-1-methylpropyl)-piperidin-4-yl]-benzyl-(4-methoxy-phenyl)-amine as a colorless oil (190 mg, 68% over 3 steps).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](=O)([O-])[O-].[K+].[K+].CN(C)C=O.C1(C)C=CC(S(OC)(=O)=O)=CC=1>C(OCC)(=O)C.CCCCCC.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: COc1ccc2c(c1)OC(=Cc1ccc(OC)c(C)c1)C2=O
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.477 g, potassium carbonate 0.583 g and dimethylformamide 5 ml, methyl p-toluenesulfonate 0.314 g was added. After the mixture was stirred for two hours at a temperature of 60° C., water 100 ml was added. The resulting compound was extracted with ethyl acetate 50 ml twice. The ethyl acetate solution was washed with a saturated sodium chloride solution 50 ml twice, dehydrated with anhydrous magnesium sulfate, and concentrated at a temperature of 40° C. under reduced pressure to obtain crude powder. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dissolved in ethyl acetate 2 ml and hexane 10 ml, and the solution was allowed to stand at room temperature for two hours. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 371.6 mg.
Reaction SMILES: [F:1][C:2]([F:21])([S:17]([O-:20])(=[O:19])=[O:18])[CH:3]([O:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].C([O:26][C:27]1[CH:32]=[CH:31][C:30]([S+:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)(C)(C)C.CS(O)(=O)=O>ClCCl>[F:21][C:2]([F:1])([S:17]([O-:20])(=[O:18])=[O:19])[CH:3]([O:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([F:5])([F:7])[F:6].[OH:26][C:27]1[CH:32]=[CH:31][C:30]([S+:33]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: CS(=O)(=O)O
Agent: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])c1ccccc1
Solvent: ClCCl
Product: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In 60 g of dichloromethane was dissolved 6.7 g of 4-tert-butoxyphenyldiphenylsulfonium 1,1,3,3,3-pentafluoro-2-benzoyloxypropane-1-sulfonate (PAG4) prepared in Synthesis Example 14. Methanesulfonic acid, 0.1 g, was added to the solution, which was heated and stirred at 40° C. for 3 hours. The organic layer was washed with 30 g of water three times, and concentrated. Diethyl ether was added to the concentrate for crystallization. The crystals were filtered and dried, obtaining the target compound in an amount of 4.9 g.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:26]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1cccc(F)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and m-fluorobenzoyl chloride, there is obtained ethyl N-(m-fluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 388 (3), 359 (13), 194 (100), 123 (46), 95 (36);
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3][CH2:2]1.CCN(CC)CC.[N:37]([CH:40]([CH3:42])[CH3:41])=[C:38]=[O:39]>C(Cl)Cl>[CH:40]([NH:37][C:38]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3][CH2:2]1)=[O:39])([CH3:42])[CH3:41]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 25° C. solution of N-[4-(piperidin-4-yl sulfamoyl)-naphthalen-1-yl]-benzamide (C-1) in CH2Cl2 was added Et3N followed by 2-isocyanato-propane. The reaction mixture was stirred at 25° C. overnight. Aqueous work-up followed by purification using reverse phase HPLC provided the title compound. 1H NMR (300 MHz, MeOD) δ 8.74 (d, 1H), 8.29 (d, 1H), 8.17 (d, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.81 (d, 1H), 7.63 (m, 5H), 3.75 (m, 3H), 3.21 (m, 1H), 2.68 (t, 2H), 1.51 (m, 2H), 1.26 (m, 2H), 1.05 (d, 6H); LC/MS (M+H)+ m/z 495.
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH:16][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:30][CH:31]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added 4-trifluoromethylbenzoyl chloride (87.5 ml, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (178 mg, 88%).