Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]([NH2:14])/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])C>O>[NH2:14][CH:5](/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)C(N)/C=C(\C)CP(=O)(O)O
Solvent: O
Product: C/C(=C\C(N)C(=O)O)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester are stirred under reflux in 70 ml of water for 19 hours. The reaction mixture is slowly cooled to room temperature, stirred in an ice bath for one hour,filtered and washed with cold water. In this manner there is obtained E-2-amino-4-methyl-5-phosphono-3-pentenoic acid in the form of the monohydrate, m.p. 163° (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([S:64](Cl)(=[O:66])=[O:65])=[C:61]([CH3:63])[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:64]([C:60]1[S:59][C:58]([NH:57][C:54](=[O:56])[CH3:55])=[N:62][C:61]=1[CH3:63])(=[O:65])=[O:66])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexa hydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dim ethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (60 mg) was reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride to give (S)-2-({(3S,8S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester according to General Procedure E. This ester (12 mg) was hydrolyzed according to General Procedure B to give the title compound (10 mg). LCMS (m/z): 959.
Reaction SMILES: ClC(Cl)(Cl)[N:3]=[C:4]=[O:5].[OH:8][CH2:9][CH2:10][N:11]1[C:16]([C:17]([C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=2)[C:22]#[N:23])=[O:18])=[C:15]([CH:28]([CH3:30])[CH3:29])[C:14](=[O:31])[N:13]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C:12]1=[O:41]>C(Cl)Cl>[C:22]([C:21]1[CH:20]=[C:19]([CH:26]=[C:25]([CH3:27])[CH:24]=1)[C:17]([C:16]1[N:11]([CH2:10][CH2:9][O:8][C:4](=[O:5])[NH2:3])[C:12](=[O:41])[N:13]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C:14](=[O:31])[C:15]=1[CH:28]([CH3:30])[CH3:29])=[O:18])#[N:23]
Reactant: O=C=NC(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2c(=O)c(C(C)C)c(C(=O)c3cc(C)cc(C#N)c3)n(CCO)c2=O)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c(C(C)C)c(C(=O)c3cc(C)cc(C#N)c3)n(CCOC(N)=O)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
Trichloro-isocyanato-methane (39 uL, 0.33 mmol, 2.0 eq) was added to 3-[3-(2-hydroxy-ethyl)-5-isopropyl-1-(4-methoxy-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl]-5-methyl-benzonitrile (76 mg, 0.165 mmol) in 2 mL of DCM. The reaction mixture was stirred at room temperature for 10 minutes. HPLC and LC-MS showed complete reaction of the starting materials. Ammonia gas was bubbled into 3 mL DCM in a test tube (keep bubbling for 5 minutes). The ammonia solution was added to the above reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated down and purified (silica gel, 0-80% EtOAC/hexane) to give a white powder (42 mg, 51%). LC-MS shows 505.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15](Cl)=[N:16][C:17]([S:19][CH3:20])=[N:18][C:11]=2[NH:10][CH2:9][CH2:8]1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1OB(O)O>>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH3:31])=[N:16][C:17]([S:19][CH3:20])=[N:18][C:11]=2[NH:10][CH2:9][CH2:8]1
Reactant: CSc1nc(Cl)c2c(n1)NCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Reactant: Cc1ccccc1OB(O)O
Product: CSc1nc2c(c(-c3ccccc3C)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCN2
Yield: 99.7 %

Procedure:
In a similar manner to Reference Example 10, 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin (Compound of Reference Example 8; 2.36 g) was reacted with 2-methylphenylboric acid (816 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-4-(2-methylphenyl)-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin (2.63 g, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7]([CH3:16])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].[N+:17]([O-])([O-:19])=[O:18].[NH4+]>S(=O)(=O)(O)O>[C:1]([NH:4][C:5]1[NH:6][C:7]([CH3:16])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1nc(-c2ccccc2)c(C)[nH]1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)c(C)[nH]1

Procedure:
Prepared analogously to Example D by reacting 2-acetylamino-5-methyl-4-phenyl-imidazole with ammonium nitrate in concentrated sulphuric acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a solution of 1-benzyl-4-piperidone (7.11 g, 37.6 mmol) in 1,2-dichloroethane (125 ml) were added 5-aminoindazole (5.00 g, 37.6 mmol), sodium triacetoxyborohydride (11.5 g, 52.6 mmol) and acetic acid (2.15 ml, 37.6 mmol) at room temperature, and stirred overnight at room temperature. Then, the reaction solution was poured into a 1N-aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/methanol=100/1) to obtain N-(1-benzyl-4-piperidinyl)-1H-indazol-5-amine (8.56 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[CH2:31][CH:30]([NH:33][CH3:34])[CH2:29][CH2:28]2>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH:30]3[CH2:29][CH2:28][C:27]4[C:32](=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][CH:26]=4)[CH2:31]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNC1CCc2cccc(OC)c2C1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cccc(OC)c3C1)CC2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane, triethylamine and 8-methoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene. Mp: 141°-143° C. (decomp.).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[C:11](=[O:35])[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=1)[C:2]1C=CC=[CH:4][CH:3]=1>ClCCl.CO>[CH2:16]([C:13]1[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:11](=[O:35])[C:10]([CH2:9][NH:8][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:15][CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1ccc(CNCc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCNCc1ccc(CCCC)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O

Procedure:
3-benzylaminomethyl-6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine, oil, Rf 0.15 (dichloromethane/methanol 95:5)
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][C:17]1[CH:29]=[C:28]([CH2:30][N:31](C2C(C)=C(C3C=CC(C(F)(F)F)=CC=3)N=CN=2)[CH2:32][CH2:33][CH3:34])[CH:27]=[CH:26][C:18]=1[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([N:31]([CH2:30][C:28]3[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:16])[CH:29]=3)[CH2:32][CH2:33][CH3:34])[C:7]=2[CH3:8])=[CH:10][CH:11]=1
Reactant: Cc1c(Cl)ncnc1-c1ccc(Cl)cc1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(Cl)cc2)c1C

Procedure:
Using 4-chloro-6-(4-chlorophenyl)-5-methylpyrimidine (167 mg, 0.7 mmol) and the synthetic procedure described for Intermediate 80. Purification by Biotage™ chromatography (Si, 40 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (116 mg).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:3][CH2:4][S:5][CH2:6][CH2:7][NH2:8].[CH3:25][S:26][C:27](SC)=[CH:28][N+:29]([O-:31])=[O:30]>C(#N)C>[CH3:25][S:26][C:27]([NH:8][CH2:7][CH2:6][S:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:28][N+:29]([O-:31])=[O:30]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCSCCN
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCSCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Yield: 78.7 %

Procedure:
A mixture of 2-(3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ylthio)ethylamine (14.0 g, 40.0 mmol, prepared as described in Example 5) and 1,1-bis(methylthio)-2-nitroethylene (6.60 g, 40.0 mmol) in 100 ml of acetonitrile was heated at reflux temperature for 5 hours. The reaction mixture was evaporated in vacuo to dryness and the remaining residue was chromatographed on silica gel, eluting with CHCl3 /MeOH (200:1) to afford 14.7 g (78.6%) of the desired compound, as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=4)[N:15]=3)[NH:7][C:6]=2[CH:23]=1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34]>CS(C)=O>[NH2:22][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH2:17][CH2:18][N:19]([S:33]([N:32]([CH3:37])[CH3:31])(=[O:35])=[O:34])[CH2:20][CH:21]=2)=[N:15][C:10]=1[C:8]1[NH:7][C:6]2[CH:23]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1ccc2nc(-c3nc(C4=CCNCC4)cnc3N)[nH]c2c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3nc(C4=CCN(S(=O)(=O)N(C)C)CC4)cnc3N)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of 3-(6-methyl-1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (58 mg, 0.1893 mmol) and triethylamine (38.31 mg, 52.77 μL, 0.3786 mmol) in DMSO (1.450 mL) was treated with N,N-dimethylsulfamoyl chloride (35.34 mg, 26.43 μL, 0.2461 mmol). The solution was stirred at RT for 16 hours and then partitioned between EtOAc and water. The aqueous layer was separated, organics dried over MgSO4 and concentrated in vacuo to give a yellow solid which was washed with MeOH and filtered to give the desired product (47 mg, 57% Yield). 1H NMR (400.0 MHz, DMSO) d 2.46 (s, 3H), 2.77 (s, 2H), 2.80 (s, 6H), 3.48 (s, 2H), 3.96 (d, J=3.0 Hz, 2H), 6.76 (s, 1H), 7.10 (s, 1H), 7.61-7.40 (m, 3H) and 8.34 (s, 1H) ppm; MS (ES+) 414
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=O)[CH2:2][CH3:3].C(Cl)[Cl:17]>P(Cl)(Cl)(Cl)=O>[Cl:17][C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: ClCCl
Reactant: CCCn1c(=O)[nH]c2ccccc2c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c(Cl)nc2ccccc2c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
181 g of 3-n-propylquinazoline-2,4-(1H,3H)-dione (0.887 mole) in 1200 ml of phosphorus oxychloride was refluxed for two days when TLC (SiO2, CH2Cl2 /2% MeOH) indicated that most of the starting material had gone. TLC was carried out by pipetting a small portion of the reaction mixture into ice-water, allowing the hydrolysis of POCl3 to occur at 0° C. for 15 min. and then extracting the cold solution with chloroform. The TLC plate when run might be expected to show a small amount of starting dione derived from hydrolysis of the imino chloride during the work up-TLC procedure.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:24])[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[C:25]1([CH:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:32][CH2:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][C:4]3([CH3:24])[CH2:8][C:7]4[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=4[O:5]3)[CH2:36][CH2:35]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(C(OCC2CCNCC2)c2ccccc2)cc1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCBr)O2
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCN1CCC(COC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 82 %

Procedure:
Using tert-butyl [2-(2-bromoethyl)-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl]carbamate and 4-[(diphenylmethoxy)methyl]piperidine, the procedure of Reference Example 58 was otherwise repeated to provide the title compound. Yield 82%.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][CH2:7][Cl:8])C.Cl.[NH2:13][CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1>C(O)(C)C>[ClH:8].[Cl:8][CH2:7][CH2:6][CH2:5][CH:4]1[C:17]2[NH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]=2[CH2:15][CH2:14][NH:13]1
Reactant: CCOC(CCCCl)OCC
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: CC(C)O
Product: ClCCCC1NCCc2c1[nH]c1ccccc21
Yield: 49.5 %

Procedure:
7 parts of γ-chlorobutyraldehyde diethyl acetal, 50 parts of isopropanol and 7.6 parts of 3-(β-aminoethyl)-indole hydrochloride were stirred for 7 hours at 83° C., and the mixture was cooled and then filtered under suction to give 5.5 parts (49.5%) of 1-(γ-chloropropyl)-1,2,3,4-tetrahydro-β-carboline hydrochloride of melting point 219°-221° C. The substance was identical to the product of Example 1.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CCOC(=O)COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(OCC(=O)OCC)cc1
Temperature: 25 °C
Yield: 103.6 %

Procedure:
Allyl bromide (3.37 g) was added to a stirred suspension of ethyl 4-hydroxyphenoxyacetate (5.14 g) [prepared by method of Moser, J.A.C.S., (1950), 72, 1413) and potassium carbonate (3.90 g) in butan-2-one (50 ml). The reaction mixture was heated at reflux for 12 hours. The reaction mixture was cooled to ambient temperature and then filtered. The filtrate was evaporated to give an oil which was purified by column chromatography on silica gel (Merck. Art. No. 7734) using a 4:1 (v/v) mixture of hexane and ethylacetate as eluent to give ethyl 4-allyloxyphenoxyacetate (6.41 g) as a colourless oil; microanalysis, found: C, 65.8; H, 7.20%; C13H16O4 requires C, 66.1; H, 6.83%; NMR (CDCl3): 1.28 (3H, t), 4.25 (2H, q), 4.48 (2H, m), 4.57 (2H, s), 5.22-5.44 (2H, m), 5.92-6.12 (1H, m) and 6.84 (4H, s).
Reaction SMILES: [NH2:1][C@H:2]([CH3:22])[CH2:3][CH2:4][N:5]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@@H:6]([C:8](OC)=[O:9])[CH3:7].C[Al](C)C.C(N(CC)CC)C>ClCCl>[CH3:7][C@@H:6]1[C:8](=[O:9])[NH:1][C@H:2]([CH3:22])[CH2:3][CH2:4][N:5]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: COC(=O)[C@@H](C)N(CC[C@@H](C)N)C(=O)OCc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CCN(C(=O)OCc2ccccc2)[C@H](C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl N-[(3R)-3-aminobutyl]-N-[(benzyloxy)carbonyl]-D-alaninate (0.5 g, 1.6 mmol) in dichloromethane (65 mL) was added trimethylaluminum (0.8 mL, 2M in toluene) and triethylamine (0.025 mL, 0.16 mmol), and the reaction mixture was stirred overnight at room temperature. Celite was added and the reaction was quenched by the dropwise addition of saturated aqueous ammonium chloride solution. The white granular solid formed was filtered and washed with dichloromethane. The filtrate was evaporated and purified by flash chromatography on a Biotage® system (silica gel, 5% methanol/dichloromethane) to yield the title compound. MS 277.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].CS(O)(=O)=O.[CH3:26][OH:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:27][CH3:26])=[O:10]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Reactant: CO
Agent: CS(=O)(=O)O
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 85 °C

Procedure:
2 g (0.00652 mol) (±)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide and 2 mL (0.0308 mol) methane sulfonic acid and 20 mL methanol were mixed and the solution was refluxed at 85° C. for 12 hrs. The excess of solvent was removed under reduced pressure. The pH was adjusted to about 9 with aq. solution of sodium bicarbonate at 0° C., and the product was extracted with 70 mL ethyl acetate. The combined organic extracts were dried over anhy. Na2SO4 and concentrated. The residue obtained was purified by column chromatography using hexane:ethyl acetate as eluent. The product thus obtained was concentrated, was stored under nitrogen atmosphere, and kept in refrigerator before converting into salt. The yield of titled product was 0.419 g (20%).
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:21]4[CH:26]=[C:25]([NH2:27])[C:24]([F:28])=[CH:23][C:22]=4[Cl:29])[C:15](=[O:20])[N:16]3[CH3:19])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:25]1[C:24]([F:28])=[CH:23][C:22]([Cl:29])=[C:21]([C:14]2[C:15](=[O:20])[N:16]([CH3:19])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:26]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2Cl)c(=O)n3C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1Cl)c(=O)n2C
Yield: 72.9 %

Procedure:
A solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 6.6 mmol) in CH2Cl2 (50 mL) was treated with TFA (20 mL) and the mixture was heated to reflux overnight. The mixture was concentrated under reduced pressure, the residue was dissolved in 10% aq. of HCl (50 mL) and the aqueous layer was washed with EtOAc. The aqueous layer was neutralized with NaHCO3 aq. solution to pH 8, and then extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (1.6 g, 72% yield) 1H NMR (300 MHz, DMSO-d6): δ 8.36 (s, 1 H), 7.66 (s, 1 H), 7.17 (d, J=10.8 Hz, 1 H), 7.05 (m, 1H), 6.71 (d, J=9.6 Hz, 1 H), 6.15 (s, 1 H), 5.30 (s, 2 H), 3.47 (s, 3 H), 3.42 (s, 1 H), 2.84 (d, J=4.4 Hz, 3 H); MS (ESI) m/z: 333.1 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[C:4](=[O:23])[CH:3]=1.S(OC)(O[C:28](SC)([S:31][CH3:32])[S:29][CH3:30])(=O)=O>C(O)(=O)C.N1C=CC=CC=1>[CH3:30][S:29][C:28]([S:31][CH3:32])=[C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([N:12]2[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]2=[O:21])[C:4]1=[O:23]
Reactant: O=C1c2ccccc2C(=O)N1n1c(=O)cc(O)c2ccccc21
Reactant: COS(=O)(=O)OC(SC)(SC)SC
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CSC(SC)=C1C(=O)c2ccccc2N(N2C(=O)c3ccccc3C2=O)C1=O
Temperature: 100 °C
Yield: 66 %

Procedure:
A solution of the product of Example 350B (0.6 g, 1.96 mmol) in acetic acid:pyridine (5:1, 15 mL) was treated with tris(methylthio)methyl methyl sulfate (prepared using the procedures in Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi)(1.6 g, 3 eq.) and heated at 100° C. for 2 hours. The reaction mixture was treated with ice, and the precipitated solids were filtered and dried in vacuum to give 0.53 g (66%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.63 (s, 6H), 7.34 (m, 1H), 7.55 (d, 1H), 7.61 (m, 1H), 8.08 (m, 5H). MS (DCI+) m/z 411 (M+H)+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.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>[F:12][C:13]([F:27])([F:28])[C:14]1[CH:15]=[C:16]([C:2]2[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: CCOC(=O)c1ccc(Br)o1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
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: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)o1
Yield: 37.6 %

Procedure:
To a solution of ethyl 5-bromofuran-2-carboxylate (100 mg, 0.46 mmol) in benzene (5 mL) were added 3,5-bis(trifluoromethyl)phenylboronic acid (141 mg, 0.55 mmol), 2M Na2CO3 (6860, 1.37 mmol), and catalytic amounts of Pd(PPh3)4 (106 mg, 0.09 mmol). The reaction mixture was refluxed for 6 hrs, diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOAc/n-Hex=1:5) to give title compound (61 mg, 38%).