Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]3[NH:24][CH2:23][C:22](=[O:25])[NH:21][N:20]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+].ClCCl>CO>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[NH:24][CH2:23][C:22](=[O:25])[NH:21][N:20]=2)=[CH:15][CH2:14]1
Reactant: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CN3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CN3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
1-[(4-Methoxyphenyl)carbonylmethyl]-4-(4,5-dihydro-1,2,4-triazin-6(1H)-one-3-yl)pyridinium bromide (300 mg, 0.74 mmol) was dissolved in methanol (5 ml), gradually added with sodium borohydride (280 mg, 7.4 mmol) under ice cooling and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue obtained was added with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain the titled compound (165 mg) as colorless plates.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][C:46]1[N:50]([CH3:51])[C:49]2[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=2[N:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:51][N:50]1[C:49]2[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=2[N:47]=[C:46]1[CH2:45][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: Cn1c(CBr)nc2ccccc21
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cn1c(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and 2-(bromomethyl)-1-methyl-1H-benzo[d]imidazole to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (70%) as a colorless solid: mp 244-246° C.; 1H NMR (300 MHz, CDCl3) δ7.95-7.86 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.49-7.40 (m, 2H), 7.32 (dd, J=7.6, 7.6 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.07 (dd, J=7.6, 7.6 Hz, 1H), 6.52-6.36 (m, 2H), 5.51 (ABq, 2H), 4.81 (ABq, 2H), 4.55 (t, J=8.6 Hz, 2H), 3.92 (s, 3H), 2.99 (t, J=8.6 Hz, 2H); MS (ES+) m/z 424.1 (M+1).
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1.[CH3:26][NH2:27].O>CC(N(C)C)=O>[CH3:26][NH:27][C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1
Reactant: CN
Reactant: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNc1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
A stirred solution of Example 5 (0.4 g, 1 mmol) in dimethyl acetamide (10 ml) was treated with methylamine (2.0M in MeOH, 4.96 ml, 1.10 mmol). The solution was heated to 150° C. in a sealed tube for 1 h. The solution was cooled to room temperature and slowly poured onto stirred iced water (100 ml). After 15 min stirring, a light orange solid was filtered. Recrystallisation from hot ethyl acetate gave the title compound in 58% yield, >95% purity. LC-MS m/z=382.0 [M+H]+; RT=2.73; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 2.89 (3H, d, J 5.0 Hz), 4.67 (2H, d, J 6.0 Hz), 5.81 (1H, s), 7.23 (1H, t, J 4.5 Hz), 7.77 (1H, d, J 8.0 Hz), 7.96 (1H, b), 8.09 (1H, d, J=5.0 Hz), 8.41 (1H, d, J=5.0 Hz), 8.36-8.50 (1H, b), 8.61 (1H, bd)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=O)=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([N:53]([CH2:56][CH3:57])[CH2:54][CH3:55])=[O:52])[CH2:42][CH2:41]1.BrCCCCCC(N(CC)CC)=O.O1C2(CCNCC2)OCC1>O>[CH2:56]([N:53]([CH2:54][CH3:55])[C:51](=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][N:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:13]([C:9]2[CH:10]=[N:11][C:12]3[C:7]([C:8]=2[NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH:26]4[CH2:27][CH2:28][N:29]([CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:30][CH2:31]4)=[O:24])=[CH:21][CH:22]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])=[O:15])[CH2:41][CH2:42]1)[CH3:57]
Reactant: CCN(CC)C(=O)CCCCCN1CCC(N)CC1
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Agent: C1CC2(CCN1)OCCO2
Agent: CCN(CC)C(=O)CCCCCBr
Solvent: O
Product: CCN(CC)C(=O)CCCCCN1CCC(NC(=O)c2cnc3c(OC)cccc3c2Nc2ccc(C(=O)NC3CCN(Cc4ccccc4)CC3)cc2)CC1

Procedure:
N-[1-[6-(Diethylamino)-6-oxohexyl]-4-piperidinyl]-8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]-phenyl]amino]-3-quinolinecarboxamide was prepared as a hygroscopic solid (1.14 hydrate) by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]-carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and 4-amino-N,N-diethylol-piperidinehexanamide as described for Example 17, Step 5. 4-amino-N,N-diethyl-1-piperidinehexanamide can be prepared from 6-bromo-N,N-diethylhexanamide (Step 1) and 1,4-dioxa-8-azaspiro[4.5]-decane as described in U.S. Pat. Nos. 3,875,165 and 4,816,464: mp 115°-120° C.; 1H NMR (Me2SO-d6, 400 MHz) δ 9.49 (s, 1 H), 8.77 (s, 1 H), 8.39 (d, J=7.5 Hz, 1 H), 8.00 (d, J=7.7 Hz, 1 H), 7.69 (d, J=8.7 Hz, 2 H), 7.56 (d, J=1 H) 7.40 (m, 1 H), 7.1-7.3 (m, 6 H), 6.87 (d, J=8.68 Hz, 2 H), 3.95 (s, 3 H), 3.7 (m, 1 H), 3.1-3.6 (m, 7 H), 2.6-2.9 (m, 4 H), 2.1-2.3 (m, 4 H), 1.98 (t, J=11.0 Hz, 2 H), 1.65-1.85 (m, 4 H), 1,1-1.6 (m, 12 H), 0.95-1.1 (doft, J=7.1Hz, 6H); Karl Fischer, 2.63% H2O
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([S:17][CH3:18])[N:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:24][C:2]2[N:7]3[N:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:10]=[C:6]3[N:5]=[C:4]([S:17][CH3:18])[N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CSc1nc(Cl)n2nc(-c3ccccc3)cc2n1
Reactant: NC1CCCC1
Product: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 80 °C
Yield: 78 %

Procedure:
4-Chloro-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazine (2.5 g, 9 mmol) was dissolved in cyclopentylamine (30 mL) and the resulting solution heated to 80° C. for 2 hours. Excess cyclopentylamine was removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give a foam. This foam was purified by silica gel chromatography (ethyl acetate:hexane 1:1) go give 2.3 g (78%) of N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4amine as a solid. 1H-NMR (CDCl3): δ 7.96 (m, 2H), 7.47 (m, 3H), 6.63 (d, 1H), 6.56 (s,1H), 4.54 (m, 1H), 2.61 (s, 3H), 2.2–2.0 (m, 2H), 1.9–1.5 (m, 6H); MS m/z 326 (M+1).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[BrH:5].[Br:6][CH:7]1[C:12](=O)[CH2:11][CH2:10][NH:9][CH2:8]1>C(O)C>[BrH:6].[BrH:5].[N:1]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[S:3][C:2]=1[NH2:4]
Reactant: NC(N)=S
Reactant: O=C1CCNCC1Br
Agent: Br
Solvent: CCO
Product: Nc1nc2c(s1)CNCC2
Yield: 84.9 %

Procedure:
4.55 g thiourea was added to 15.2 g 3-Bromo-piperidin-4-one hydrobromide in 152 mL ethanol and refluxed for 20 h. The reaction was cooled and the solid was filtered, washed with ethanol and dried to give 15.8 g of the desired product., (M+H)+: 184
Reaction SMILES: [C:1]([CH:3](P(OCC)(OCC)=O)[CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2].[H-].[Na+].[N+:26]([C:29]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][C:30]=1[CH:31]=O)([O-:28])=[O:27].C(OCC)(=O)C>C1COCC1>[C:1]([C:3](=[CH:31][C:30]1[CH:33]=[C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:36][C:29]=1[N+:26]([O-:28])=[O:27])[CH:4]([CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2]
Reactant: CCOP(=O)(OCC)C(C#N)C(CCC(=O)O)C1CCOCC1
Reactant: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC(=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(CCC(=O)O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-cyano-5-(diethoxy-phosphoryl)-4-(tetrahydro-pyran-4-yl)-pentanoic acid (2.68 g, 7.7 mmol) in THF (300 mL), sodium hydride (60%, 1.24 g) was added portionwise at room temperature. 2-Nitro-5-phenoxy-benzaldehyde (1.9 g, 7.7 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the resulting solution washed with saturated aqueous NH4Cl solution. The organic phase was separated, dried with MgSO4, and filtered. The filtrate was evaporated in vacuo to yield an oil which was triturated with heptane to yield the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH:12]=O)([CH3:6])[C:3]#[C:4][CH3:5].[NH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:19]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:27]([O:26][C:24]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][CH2:12][C:11]2[CH:14]=[C:7]([C:2]([CH3:6])([CH3:1])[C:3]#[C:4][CH3:5])[CH:8]=[CH:9][C:10]=2[O:15][CH3:16])[C@@H:19]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: CC#CC(C)(C)c1ccc(OC)c(C=O)c1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: CC#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1

Procedure:
This compound was prepared from Compound 55 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Sn](C)(C)C.O>CN(C)C=O>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: C[Sn](C)(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccccn3)c2)cc1
Yield: 34.5 %

Procedure:
Methyl 4-[(3-bromophenyl)methoxy]benzenepropanoate (0.70 g, 2.0 mmol) and 2-pyridyltrimethyltin (0.60 g, 2.4 mmol) were dissolved in N,N-dimethylformamide (15 mL) and, after argon substitution, dichlorobistriphenylphosphinepalladium (II) (0.10 g, 0.070 mmol) was added. The reaction mixture was heated under reflux overnight under an argon atmosphere. The reaction mixture was cooled, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5:1) to give the title compound (0.24 g, yield 35%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br>CN1C(=O)CCC1.CCOCC>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1ccc(F)cc1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1(c2ccc(F)cc2)CCOCC1
Temperature: 0 °C
Yield: 97 %

Procedure:
A mixture of NaH (1.7 g, 71 mmol) in 100 mL NMP stirred at 0° C., was treated dropwise with a mixture of ethyl 2-(4-fluorophenyl)acetate (5.2 g, 29 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (6.6 g, 29 mmol) in 20 mL ether. The mixture was allowed to warm to room temperature and stirred for 5 hours, M+1=253. The mixture was then carefully quenched with 100 mL H2O, and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The combined organic layers were then dried over anhydrous Na2SO4 and concentrated in vacuo to give 7.1 g of the crude product as a pale yellow oil. MS (m/z)=253 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:15].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:15])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2cc(F)ccc2n1CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2cc(F)ccc2n1CCCOS(C)(=O)=O
Temperature: 25 °C

Procedure:
To a stirred, cold mixture (-25° C.) of 1-(3-hydroxy-propyl)-2-methyl-5-fluoro-1H -benzimidazole (1.99 gm), triethylamine (1.47 ml) and methylenechloride (40 ml) is dropwise added a solution of methanesulfonylchloride (0.96 ml) in 15 ml CH2Cl2. After complete addition, the mixture is warmed to ambient temperature, extracted with water (2×20 ml), dried over Na2SO4 and concentrated to a thick brown oil consisting of crude 1-(3-methanesulfonyloxy-propyl)-2-methyl-5-fluoro-1H -benzimidazole.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18]O)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(Cl)(Cl)(Cl)[Cl:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][Cl:21])[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: OCCCN1CCN(c2cccc3sccc23)CC1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: ClCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C

Procedure:
3.56 g (12.9 mmol) of 3-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol was suspended in 30 ml of methylene chloride, and carbon tetrachloride (30 ml) and triphenyl phosphine (4.06 g, 15.5 mmol) were added thereto followed by stirring under reflux for 3 hours. The reaction mixture was cooled to room temperature, then methanol and methylene chloride were added thereto so as to make the mixture uniform. Silica gel (30 g) was added to the uniform solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: 300 g, n-hexane:ethyl acetate=2:1), then concentrated under reduced pressure to obtain 1-benzo[b]thiophen-4-yl-4-(3-chloropropyl)piperazine (2.36 g) as colorless oil.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:65][C:66]1[N:71]=[CH:70][C:69]([C:72](O)=[O:73])=[CH:68][CH:67]=1>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:72]([C:69]1[CH:70]=[N:71][C:66]([CH3:65])=[CH:67][CH:68]=1)=[O:73]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)cn1
Yield: 62.1 %

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (100 mg, 0.324 mmol) in DMF (5 ml) was added DIPEA (0.170 ml, 0.973 mmol), HOBT.H2O (49.7 mg, 0.324 mmol), HBTU (123 mg, 0.324 mmol) and 6-methyl-3-pyridinecarboxylic acid (44.5 mg, 0.324 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated in vacuo, DCM (50 ml) was added and the solution was washed with NfaHCO3 (5 ml×2). The organic layer was dried with dried magnesium sulphate which was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual oil was dissolved in 1:1 MeCN/DMSO (1.8 ml) and purified by MDAP in two batches. The fractions containing the desired product were combined and evaporated to dryness in vacuo. The residue was azeotroped with toluene to remove any remaining water to yield the title compound (86 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([I:14])[CH:10]=[C:9]1[C:15]([NH2:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O>CN(C)C=O.N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([I:14])[CH:10]=[C:9]1[C:15]#[N:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(I)cc(C(N)=O)n1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1c(I)cc(C#N)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 129B (400 mg) in N,N-dimethylformamide (6 mL) and pyridine (0.6 mL) at (PC was added dropwise oxalyl chloride (0.31 mL). The mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate and washed with saturated NaHCO3 and water extensively. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography, and eluted with dichloromethane to provide the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[N+:11]([C:14]1[C:15]([NH2:21])=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]>C(O)C>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]1[NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([N+:11]([O-:13])=[O:12])[C:15]=2[N:21]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: COc1ccccc1C=O
Solvent: CCO
Product: COc1ccccc1-c1nc2c([N+](=O)[O-])cccc2[nH]1
Yield: 35.3 %

Procedure:
A solution of o-anisaldehyde (0.789 ml, 6.53 mmol) and 3-nitro-o-phenylenediamine (1 g, 6.53 mmol) in ethanol (30 ml) was heated to 90° C. for 20 hours in a sealed tube. The red reaction mixture was taken to dryness and purified by silica gel chromatography (Biotage 40M, 75% DCM in hexanes to 100% DCM) to give 163 (0.62 g, 2.303 mmol, 35.3% yield) as yellow solid. LRMS (ESI): (calc.) 269.3 (found) 270.1 (MH)+.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:23]([O:25][CH3:26])=[O:24])=[CH:14][CH:13]=1)([O-])=O>O.CCO>[NH2:9][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:23]([O:25][CH3:26])=[O:24])=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccn1-c1ccc([N+](=O)[O-])cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cccn1-c1ccc(N)cc1
Yield: 54.7 %

Procedure:
Sodium hydrosulphite (2.08 g, 10.15 mmoll) in water (7.5 mL) was added to a refluxing solution of (i) (1 g, 4.06 mmol) in EtOH (15 mL). After 5 minutes another solution of sodium hydrosulphite (2.08 g, 10.15 mmoll) in water (7.5 mL) was added. The mixture refluxed for 5 min After that time the mixture was poured onto water. The reaction mixture was extracted with EtOAc and DCM/iPrOH. The organic fractions were dried (MgSO4), filtered and concentrated in vacuo to give a residue that was purified by flash chromatography on silica gel, eluting with a MeOH gradient in DCM to afford the desired product (ii) (480 mg). 1H NMR (400 MHz, DMSO) δ 7.06 (dd, J=2.5, 1.9 Hz, 1H), 6.96-6.90 (m, 3H), 6.59-6.53 (m, 2H), 6.22 (dd, J=3.9, 2.6 Hz, 1H), 5.25 (s, 2H), 3.60 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1.[CH3:31][N:32]([CH2:34][CH2:35]Cl)[CH3:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:35][CH2:34][N:32]([CH3:33])[CH3:31])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)cc(OC)c1OC
Reactant: CN(C)CCCl
Product: COc1cc(-c2nc3ccc(OCCN(C)C)cc3n2Cc2ccccc2Br)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 114 with 2-(N,N-dimethylamino)ethyl chloride essentially as previously described. mp 152° C., NMR, IR, MS 539, 541.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1.[N:20]1[CH:28]=[C:27]2[C:23]([N:24]=[CH:25][NH:26]2)=[N:22][CH:21]=1.[H-].[Na+]>CN(C)C=O>[N:20]1[CH:28]=[C:27]2[C:23]([N:24]([CH2:2][C:3]3[CH:4]=[CH:5][C:6]4[S:11][C:10]5[N:12]=[CH:13][CH:14]=[N:15][C:9]=5[N:8]([CH2:16][O:17][CH3:18])[C:7]=4[CH:19]=3)[CH:25]=[N:26]2)=[N:22][CH:21]=1.[N:20]1[CH:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[CH2:2][C:3]2[CH:4]=[CH:5][C:6]3[S:11][C:10]4[N:12]=[CH:13][CH:14]=[N:15][C:9]=4[N:8]([CH2:16][O:17][CH3:18])[C:7]=3[CH:19]=2)=[N:22][CH:21]=1
Reactant: c1ncc2[nH]cnc2n1
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1c2cc(Cn3cnc4cncnc43)ccc2Sc2nccnc21
Product: COCN1c2cc(Cn3cnc4ncncc43)ccc2Sc2nccnc21

Procedure:
In accordance with the procedure of Example 1094, 740 mg of 8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was reacted with 460 mg of purine in the presence of sodium hydride (60% oily) in N,N-dimethylformamide (10 ml). The two isomers thus obtained were purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 320 mg of 8-(purin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 125 mg of 8-(purin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine each as yellow crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O>[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([O:38][CH2:2][C:3]3[CH:20]=[CH:19][CH:18]=[C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:4]=3)=[CH:34][C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CCCOC(=O)c1cc(=O)c2cc(O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cc(=O)c2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1
Yield: 28.2 %

Procedure:
A mixture of 3.47g of 2-((3-chloromethylphenoxy)methyl)quinoline, 3.04g of 2-carbopropoxy-6-hydroxy-4-oxo-4H-1-benzopyran, 1.69g of potassium carbonate and 1 ml of dimethylformamide is refluxed in 50 ml of acetone for 41 hours. The mixture is concentrated in vacuo and the residue is dissolved in water. This solution is neutralized with diluted hydrochloric acid and the resulting solid is filtered off and purified by flash silica gel chromatography in propanol-dimethylformamide to give 1.71 g of 2-carbopropoxy-6-(3-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran as a white solid having an m.p. of 109°-10° C.