Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[N:11][C:10]=2Br)[CH2:5][CH2:4]1)[CH3:2].C([Li])(C)(C)C.CN(C)[CH:27]=[O:28].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[N:11][C:10]=2[CH2:27][OH:28])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCN(c2c(Br)ncc3ccccc23)CC1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1CCN(c2c(CO)ncc3ccccc23)CC1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A solution of 4-(4-ethylpiperidin-1-yl)-3-bromoisoquinoline (1.03 g) in tetrahydrofuran (20 ml) was cooled to −78° C., followed by the dropwise addition of 1.7M tert-butyllithium (3 ml). Fifteen minutes later, N,N-dimethylformamide (0.5 ml) was added thereto and the temperature of the reaction solution was raised to room temperature. To the reaction solution was added an aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate, followed by washing with water and brine, drying and evaporating. The resulting residue was dissolved in methanol (15 ml), and reacted with sodium borohydride (0.4 g). The solvent was removed, the resulting residue was extracted with ethyl acetate extraction, followed by washing with water and brine, drying and evaporating. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 4-(4-ethylpiperidin-1-yl)-3-hydroxymethylisoquinoline (0.46 g, 52.7%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=O)[NH:12][CH:13]([C:30]2[C:35]([Cl:36])=[N:34][CH:33]=[CH:32][N:31]=2)[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH2:7][CH2:6]1)=[O:4].O=P(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:31]3[CH:32]=[CH:33][N:34]=[C:35]([Cl:36])[C:30]3=[C:13]([C:14]3[CH:23]=[C:22]4[C:17]([CH:18]=[CH:19][C:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:21]4)=[CH:16][CH:15]=3)[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn32)CC1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A CH2Cl2 solution (2 mL) of trans-4-{[(3-chloropyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-cyclohexanecarboxylic acid methyl ester (2.3 g, 4.5 mmol) in a round bottom flask equipped with a condenser was charged with POCl3 (15 mL) and stirred at 80° C. for 72 h. The reaction mixture was concentrated in vacuo to a foam, cooled to 0° C., and charged with cold 2M NH3 in isopropanol to basic pH. The mixture was concentrated in vacuo to solids and partitioned between EtOAc and water. The organic layer was washed with water (1×), brine (1×), dried over Na2SO4, filtered, and concentrated to a brown oil. The resulting residue was purified by silica gel chromatography (CH2Cl2 to 1%˜7N NH3 in MeOH/CH2Cl2) to provide the desired product as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.62-1.73 (m, 2H), 1.92-2.02 (m, 2H), 2.15-2.27 (m, 4H), 2.44-2.60 (m, 1H), 2.99-3.08 (m, 1H), 3.72 (s, 3H), 7.39 (d, 1H, J=5.2 Hz), 7.45-7.50 (m, 1H), 7.51-7.57 (m, 2H), 7.61 (d, 1H, J=5.2 Hz), 7.85-7.93 (m, 3H), 8.19 (d, 2H, J=7.6 Hz), 8.27 (d, 1H, J=8.4 Hz), 8.50 (s, 1H); MS (ES+): m/z 496.9 [MH+]; HPLC: tR=3.6 min (Micromass Platform II, nonpolar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[CH3:13][CH:14]1[CH:19](O)[CH2:18][CH2:17][N:16]([C:21]2[N:22]=[N:23][CH:24]=[CH:25][N:26]=2)[CH2:15]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH:19]1[CH2:18][CH2:17][N:16]([C:21]2[N:22]=[N:23][CH:24]=[CH:25][N:26]=2)[CH2:15][CH:14]1[CH3:13]
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Reactant: CC1CN(c2nccnn2)CCC1O
Product: CC1CN(c2nccnn2)CCC1Oc1cc(C(F)(F)F)ccc1Cl

Procedure:
Compound 37 is prepared from 2-chloro-5-trifluoromethylphenol and intermediate 5c according to synthesis method 3 under the operating conditions described for example 8 (38% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]1([NH:31][CH2:32][CH2:33]O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:33][CH2:32][NH:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: OCCNc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(CCNc2ccccc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a THF solution (2 ml) of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, 2-(phenylamino)ethanol (19 mg, 0.13 mmol), triphenylphosphine (55 mg, 0.21 mmol) was added diethyl azodicarboxylate (0.09 ml, 42% wt in toluene, 0.21 mmol). After 1 h, the reaction mixture was concentrated. The crude material was purified by preparative HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(2-(phenylamino)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (14.4 mg, 23%) as a yellow solid. MS M+H=476; 1H NMR (CDCl3) δ 8.20 (1H), 7.41-7.20 (11H), 7.10 (2H), 4.51 (2H), 3.91 (2H).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:20]=[O:21].Cl>O1CCCC1.CCCCCC>[O:10]1[C:4]2[CH:3]=[C:2]([CH:20]=[O:21])[CH:12]=[CH:11][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)OCCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2c(c1)OCCCC2
Temperature: 25 °C
Yield: 105.8 %

Procedure:
To a solution of 2.01 g (8.8 mmol) of 8-bromo-2,3,4,5-tetrahydro-1-benzoxepine in 54 mL of anhydrous tetrahydrofuran and 13.5 mL of hexane under nitrogen cooled in a dry ice/acetone bath was added dropwise 4.1 mL (10.2 mmol, 1.15 equiv) of 2.5M n-butyllithium in tetrahydrofuran, keeping the internal temperature <−65° C. The mixture was stirred with cooling for 45 minutes. A solution of 1.03 mL (13.3 mmol, 1.5 equiv) dimethylformamide in 9 mL of anhydrous tetrahydrofuran was added dropwise over 5 minutes. The mixture was stirred overnight while warming to ambient temperature. The reaction mixture was poured into 81 mL of 2N HCl, and the layers were separated. The aqueous layer was extracted with 3×85 mL of ether. The combined organic layer was washed with 75 mL each of water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1.64 g of a yellow oil. Purification by flash chromatography (5-40% ethyl acetate in hexanes) gave the product as a colorless oil. MS (m+1)=177.2; 1H NMR (400 MHz, CDCl3) 9.92 (s, 1H), 7.49 (m, 2H), 7.29 (d, 1H, J 7.5 Hz), 4.03 (m, 2H), 2.89 (m, 2H), 2.00 (m, 2H), 1.76 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:10]([CH2:24][CH2:25]O[Si](C(C)(C)C)(C)C)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:39][C:40]([S:43]([N:45]=[C:46]1[CH2:49][O:48][CH2:47]1)=[O:44])([CH3:42])[CH3:41]>CCCCCC.C1COCC1>[CH:24]([N:10]1[C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)=[CH:12][C:8]([C:4]2[CH:3]=[C:2]([C:46]3([NH:45][S:43]([C:40]([CH3:39])([CH3:41])[CH3:42])=[O:44])[CH2:49][O:48][CH2:47]3)[CH:7]=[CH:6][CH:5]=2)=[N:9]1)=[CH2:25]
Reactant: CC(C)(C)[Si](C)(C)OCCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cn1nc(-c2cccc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-{3-(3-Bromophenyl)-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-1-yl}-1-(tert-butyldimethylsilyloxy)ethane (4.2 g, 7.8 mmol) was dissolved in 40 mL of hexane (dried over Na2SO4) and 15 mL THF (freshly distilled from CaH2). The solution was sparged with argon and cooled to −78° C. To the stirred solution was added nBuLi (6.21 mL of a 2.5 M solution in hexanes, 15.5 mmol) and the mixture was stirred for 15 min. LCMS showed incomplete reaction, so more nBuLi (1.0 mL, 2.5 mmol) was added and the mixture was stirred for 10 min. 2-Methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1.4 g, 7.8 mmol) was dissolved in 10 mL of THF (freshly distilled from CaH2) and cooled to −78° C. The cold solution of sulfinamide was added via cannula into the cold solution of anion. The resulting mixture was stirred for 10 min, then quenched by addition of 20% aqueous NH4Cl solution. The mixture was warmed to ambient temperature and extracted with EtOAc. The EtOAc layer was washed with water and brine, then dried over MgSO4, and the solvents were removed under reduced pressure. The residue was chromatographed on a 120 g silica gel column using 0-100% EtOAc:hexanes over 36 min at 85 mL/min. The product-containing fractions were combined and the solvents were removed under reduced pressure to give N-{3-[3-(1-ethenyl-5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl)phenyl]oxetan-3-yl}tert-butylsulfinamide as an oil. Calcd (M+1)+: 506.6. Found: 506.3
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([NH2:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[I:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:10][C@@H:8]([CH3:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: C[C@H](N)Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: C[C@@H](Cc1ccccc1)N=Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-1-phenylpropan-2-amine (0.500 g, 3698 μmol) in benzene (5 mL) was added 4-iodobenzaldehyde (858 mg, 3698 μmol) and MgSO4 (1.000 g, 8308 μmol) and the suspension stirred at RT 4 h. The suspension was filtered and the solid washed with benzene (2×2 mL). The combined filtrates were concentrated to give (S)—N-(4-iodobenzylidene)-1-phenylpropan-2-amine as a yellow oil which was used without purification in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([N:10]=[C:11]=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:38]=[CH:37][C:23]([O:24][C:25]2[C:34]3[NH:33][C:32](=[O:35])[C:31]([CH3:36])=[N:30][C:29]=3[N:28]=[CH:27][CH:26]=2)=[CH:22][C:21]=1[F:39]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:19][C:20]2[CH:38]=[CH:37][C:23]([O:24][C:25]3[C:34]4[NH:33][C:32](=[O:35])[C:31]([CH3:36])=[N:30][C:29]=4[N:28]=[CH:27][CH:26]=3)=[CH:22][C:21]=2[F:39])=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Cc1nc2nccc(Oc3ccc(N)c(F)c3)c2[nH]c1=O
Product: Cc1nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c(F)c3)c2[nH]c1=O

Procedure:
Method F3 was used with 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole and 8-(4-Amino-3-fluorophenoxy)-3-methylpyrido[2,3-b]pyrazin-2(1H)-one.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:9])[C:5]([F:8])([F:7])[F:6].S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH2:2][NH:3][C:4](=[O:9])[C:5]([F:8])([F:7])[F:6]
Reactant: O=C(NCO)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(NCCl)C(F)(F)F

Procedure:
51.7 grams (g) (0.36 mole) of N-hydroxymethyl trifluoroacetamide were dissolved in 350 milliliters (ml) dichloromethane in a round-bottom flask equipped with a magnetic stirrer and reflux condenser. Thirty-three ml (0.45 mole) thionyl chloride were added dropwise with vigorous stirring. The reaction mixture was heated at reflux until the gas evolution ceased. The resulting mixture was then stripped under reduced pressure to yield the desired product.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][N:33]=[C:32]2[O:39][CH2:40][CH:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1>ClC(Cl)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:47][CH:44]3[CH2:45][CH2:46][CH:41]([CH2:40][O:39][C:32]4[C:31]5[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[CH:30]=5)[N:35]=[CH:34][N:33]=4)[CH2:42][CH2:43]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COc1ccc2ncnc(OCC3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc2ncnc(OCC3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 2 h

Procedure:
2,3-Dihydro-benzo[1,4]dioxin-6-carbaldehyde (0.045 g, 0.27 mmol) and then sodium triacetoxyborohydride (0.08 g, 0.377 mmol) were added to a solution of 4-(6-methoxyquinazolin-4-yloxymethyl)-cyclohexylamine (0.07 g, 0.25 mmol) in dichloroethane (1 ml). The reaction mixture was stirred for 2 hours and then filtered over Hydromatrix (wetted with NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 9/1 and then dichloromethane/MeOH 6/1).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N+:20]([O-])=O)[C:6]1=[O:23])[CH:2]=[CH2:3].N1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:6]1=[O:23])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)c2ccc([N+](=O)[O-])c3cc(C)cc(c23)C1=O
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCON1C(=O)c2ccc(N3CCCC3)c3cc(C)cc(c23)C1=O
Yield: 96.2 %

Procedure:
Following the procedure of Example W1, 2-allyloxy-5-methyl-7-nitro-benzo[de]isoquinoline-1,3-dione (0.52 g, 1.7 mmol, from Example 12), pyrrolidine (0.23 g, 3.2 mmol), triethyl amine (0.65 g, 6.4 mmol) in DMF (5 mL) were reacted to give 0.55 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:19]([S:22](Cl)(=[O:24])=[O:23])([CH3:21])[CH3:20]>C(Cl)Cl.N1C=CC=CC=1>[C:16]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([NH:1][S:22]([CH:19]([CH3:21])[CH3:20])(=[O:24])=[O:23])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)C(C)C)c1
Reaction time: 72 h
Yield: 29.9 %

Procedure:
To a stirred solution of 1-(3-amino-4-benzyloxy-phenyl)-ethanone (EP 0 659 737) (30 g, 125.0 mmol) in CH2Cl2 (500 mL) and pyridine (250 mL) was added dropwise isopropylsufonyl chloride (28.6, 200 mmol) at room temperature. The reaction was stirred for 3 days under nitrogen atmosphere. The mixture was diluted with CH2Cl2 (700 mL) and washed with 1N hydrochloric acid, water, dried over Na2SO4, and concentrated. The product was purified by flash silica gel chromatography eluting with ethyl acetate/hexanes to give the title compound as a white solid (13 g, 30%); 1H NMR (300 MHz, CDCl3) δ 1.35(d, J=6.9 Hz, 6 H), 2.56(s, 3 H), 3.25–3.45(m, 1 H), 5.18(s, 2 H), 6.75(brs, 1 H), 7.02 (d, J=8.6 Hz, 1 H), 7.30–7.50(m, 5 H), 7.70(dd, J=8.6, 2.1 Hz, 1 H), 8.18 (d, J=2.1 Hz, 1 H); MS (ES) m/z: 364.9 ((M+NH4)+, 100%; HRMS Calcd. for C18H22NO4S(MH+): 348.1264. Found: 348.1259.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:23]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccncc2[N+](=O)[O-])C1
Yield: 99 %

Procedure:
The method of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, (R)-3-N-Boc-amino piperidine and diisopropylethylamine yielding (R)-tert-butyl 1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (99%). LCMS (m/z): 323.1 (MH+); LC Rt=2.13 min.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20](/[CH:21]=[N:8]/[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(/C=N/C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a solution of diphenylmethanamine (3.00 g, 16.4 mmol) in methanol (80 mL) was added 4-methoxybenzaldehyde (2.45 g, 18.0 mmol) and sodium carbonate (2.60 g, 24.6 mmol). The reaction mixture was stirred at room temperature for 16 h prior to removal of all solvents under vacuum. The residue was then diluted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford compound 39 as a white solid (3.62 g, 73%). LRMS (ESI): (calc.) 301.4 (found) 302.4 (MH)+.
Reaction SMILES: [CH:1]1[NH:5][CH:4]=[C:3]2[C:6](=[O:10])[O:7][CH2:8][CH2:9][C:2]=12.CN(C)[CH:13]=[O:14].P(Cl)(Cl)(Cl)=O>ClCCl>[O:10]=[C:6]1[C:3]2[CH2:2][CH2:1][N:5]([CH:13]=[O:14])[C:4]=2[CH2:9][CH2:8][O:7]1
Reactant: O=C1OCCc2c[nH]cc21
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=CN1CCC2=C1CCOC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
6,7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one (5 g, 36 mmol) was formulated under standard Vilsmeier reaction using N,N-dimethylformamide (DMF, 1.2 eq.) and phosphorus oxychloride (POCl3, 1.1 eq.) in dichloromethane. The above mixture was stirred at room temperature for 1 hour. The precipitate salt was filtered, washed with dichloromethane, suspended in water and made basic with 6 N sodium hydroxide to pH=12. The mixture was stirred for 5 minutes and filtered. The solid was washed with ethanol/water mixture (1:1) to give 3.5 g (58%) of 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4]pyrrole-1-carbaldehyde.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:26])[C:23](=[NH:25])[NH2:24])[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[S:34](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O>C(Cl)Cl>[NH2:25][C:23]1[C:22]([NH:21][CH2:20][CH2:19][CH2:18][O:17][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:10][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[N:16]=2)=[N:26][S:34][N:24]=1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Reactant: N=C(N)C(=N)NCCCOc1cccc(CN2CCCCC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nsnc1NCCCOc1cccc(CN2CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the crude product prepared in Step B in 80 ml of CH2Cl2 and containing 7.69 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (7.35 g; 18.5 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 50 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product. The product was purified by flash chromatography on 100 g of silica gel (230-400 mesh) using ethyl acetate-methanol (95:5) as the eluent to give 3.63 g of the title compound as a viscous oil. Treatment of the product with one equivalent of cyclohexyl sulfamic acid in acetone gave the cyclohexyl sulfamate salt of the title compound, mp 125.5°-131° C.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=O)[CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH2:20]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:21]1[CH:29]=[CH:28][C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11]([N:33]3[CH2:34][CH2:35][N:30]([CH2:20][C:21]4[CH:29]=[CH:28][C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=4)[CH2:31][CH2:32]3)=[CH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2Sc2ccccc21
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)C=C(N1CCN(Cc3ccc4c(c3)OCO4)CC1)c1ccccc1S2
Temperature: 25 °C
Yield: 17 %

Procedure:
To a stirred solution of 2-nitro-10-oxo-dibenzo[b,f]thiepine (0.54 g, 2.00 mmol) and 1-piperonylpiperazine (2.04 g, 9.26 mmol) in toluene (15 mL) was added titanium tetrachloride (0.24 mL, 2.2 mmol) at room temperature under argon. The resulted mixture was heated at reflux for 3.5 h and then cooled down to room temperature. The whole mixture was poured into a saturated sodium bicarbonate solution (50 mL). After separation, the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic solution was dried (MgSO4), filtered and concentrated in vacuo to dryness. The residue was subjected to column chromatography using ethyl acetate/hexanes (1/2) as eluent. Thus 0.161 g (17%) of the title compound was obtained as a yellow solid; m.p. 188°-190° C.; MS 474 (M+ 1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[OH-].[Na+].C1COCC1.Cl>CO>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(N)c(NC(=O)c2ccc(OC)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cc(C(=O)O)ccc2N)cc1
Yield: 97.2 %

Procedure:
A suspension of 107 (400 mg, 1.33 mmol) and 1M NaOH (2.7 ml, 2.66 mmol) in 1:1 THF:MeOH (6 ml) was heated at 50° C. for 16 h. HCl 1M was added to reach pH=4 and the solid was filtered to give 370 mg (97%) of compound 108 as a white solid. 1H NMR: (DMSO) δ (ppm): 9.52 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.71 (d, J=2.0 Hz, 1H), 7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 6.74 (d, J=8.4 Hz, 1H), 5.69 (s, 2H), 3.83 (s, 3H). MS: (calc.) 361.1; (obt.) 362.3 (MH)+.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:18][C:19]1[C:34]([Cl:35])=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:24])=[C:21]([OH:36])[CH:20]=1.Br[CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[C:44]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]2[C:42]1=[O:51]>C(#N)C>[NH2:18][C:19]1[C:34]([Cl:35])=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[O:24])=[C:21]([O:36][CH2:38][CH2:39][CH2:40][N:41]2[C:45](=[O:46])[C:44]3=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]3[C:42]2=[O:51])[CH:20]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a suspension of the tetra-n-butylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (15.8 g, 30 mmoles) (prepared in Preparation 3) in acetonitrile (50 ml) was added N-(3-bromopropyl)phthalimide and the mixture stirred for 16 hours at ambient temperature and 1 hour at 65°-70° C. This was concentrated in vacuo and the residue partitioned between water and a 1:1 mixture of ether and methylene chloride. The organic phase was washed several times with water, dried and concentrated to small volume causing crystallization. This was filtered and the solid washed with ether to give 12.3 g (86.7%) of the title product as white solid, mp. 141°-143°.