Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH:15]=[C:11]([CH2:12][OH:13])[CH:10]=1)[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)c1cc(CO)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(benzyloxy)-5-(methoxycarbonyl)benzoic acid (1 eq.) from the previous step in THF (0.2 M) at 0° C. was added borane-dimethylsulfide (1.5 eq.) and stirred at rt for 18 h. Additional borane-dimethylsulfide (3 eq.) was added and the reaction was stirred for another 2 h at rt. The reaction was slowly quenched with methanol and then concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, and brine. The organic extract was dried over MgSO4 and concentrated in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[N+:9]([O-])([OH:11])=[O:10]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1F
Product: Cc1cc([N+](=O)[O-])ccc1F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
30 g of 2-fluoro-toluene were added at -15° C. over two hours to 33 ml of nitric acid and the mixture was stirred at -15° C. for one hour and was then allowed to rise to 20° C. The reaction mixture was poured into ice and was extracted with ether. The organic phase was washed with water, dried and evaporated to dryness. The residue was rectified to obtain 34.4 g of 2-fluoro-5-nitro-toluene with a boiling point of 100°-101° C. at 10 to 11 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:19])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:6][CH:7]=1.C[Li].C([Li])(C)(C)C.[B:27](OC)([O:30]C)[O:28]C>O1CCCC1.CCCCC>[CH2:12]([NH:11][C:9](=[O:10])[N:8]([C:4]1[CH:3]=[C:2]([B:27]([OH:30])[OH:28])[CH:7]=[CH:6][CH:5]=1)[CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COB(OC)OC
Reactant: CCCCCCCNC(=O)N(C)c1cccc(Br)c1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCNC(=O)N(C)c1cccc(B(O)O)c1
Yield: 36 %

Procedure:
In a manner similar to that of Example (18a), by reaction of 113 g (0.345 mol, 1 eq) of 1-(3-bromophenyl)-3-heptyl-1-methylurea in 1.13 L of tetrahydrofuran, 127 mL (0.38 mol, 1.1 eq) of methyllithium, 530 mL (0.76 mol, 2.2 eq) of a 1.7M solution of tert-butyllithium in pentane and 97 mL (0.904 mol, 2.2 eq) of trimethyl borate, and after purification by chromatography on silica gel (50/50 heptane/ethyl acetate) and crystallization from ethyl acetate/heptane, 36.0 g of 3-(3-heptyl-1-methylureido)phenylboronic acid are obtained in the form of a pinkish powder. Yield=36%
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:28])[CH3:27].O>C(O)C>[CH2:26]([NH:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH3:27]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (321 mg, 2.32 mmol) and aqueous ethylamine solution (ca. 70%, 149 mg, 2.32 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (310 mg, 94.3% yield).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8](B(O)O)[CH:7]=[CH:6][C:5]=12.I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[N:3]1[O:2][N:1]=[C:5]2[CH:6]=[CH:7][C:8]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=3)=[CH:9][C:4]=12
Reactant: OB(O)c1ccc2nonc2c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc3nonc3c2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of Benzo[c][1,2,5]oxadiazole-5-boronic acid (18 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA44. ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)([O-])=O.[C:20]([NH:27][C@:28]([CH3:34])([C:31](O)=[O:32])[CH2:29][OH:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCN(C(C)C)C(C)C>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:18]=[CH:19][C:4]([NH:1][C:29]([C@:28]([NH:27][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:34])[CH2:31][OH:32])=[O:30])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCCCCc2cccs2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@](C)(CO)C(=O)Nc1ccc(OCCCCc2cccs2)cc1
Yield: 66.8 %

Procedure:
This compound was synthesized from 2-(4-(4-nitrophenoxy)butyl)thiophene (280 mg), N-(Boc)-α-methylserine (205 mg), HATU (442 mg), and DIPEA (506 μl) following the procedure described in Example 5(A) to yield 280 mg product (62% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 7.44 (m, 2H), 7.29 (m, 1H), 6.9 (m, 1H), 6.84–6.81 (m, 3H), 5.00 (t, 1H), 3.93 (t, 2H), 3.61 (m, 2H), 2.84 (t, 2H), 1.73 (m, 4H), 1.48 (overlapping singlets, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[CH3:15][C:10]1([CH3:16])[C:11]([CH3:14])([CH3:13])[O:12][B:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:24](=[O:26])[CH3:25])=[N:3][CH:4]=2)[O:9]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (120 mg) in dry DCM (3 ml) and triethylamine (1.5 equiv., 114 uL) was added acetic anhydride (1.1 equiv., 57ul) and the reaction mixture was stirred at room temperature overnight. Dichloromethane/brine extraction and purification on silica gave 66 mg of N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]-acetamide.
Reaction SMILES: [OH:1][C@@H:2]1[CH:6]=[CH:5][C@H:4]([O:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1>CCOC(C)=O.CCCCCC>[OH:1][C@H:2]1[CH:6]=[CH:5][C@H:4]([O:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3]1
Reactant: O[C@@H]1C=C[C@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O[C@H]1C=C[C@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Yield: 77 %

Procedure:
Compound 37 was subjected to general procedure J. TLC: Rf=0.36 (10% EtOAc/Hexane). 1H NMR (400 MHz, DMSO): δ2.00 (m, 1H), 2.15 (m, 1H), 4.95 (m, 1H), 5.40 (m, 1H), 5.95 (m, 1H), 6.05 (m, 1H), 7.30-7.60 (m, 15H), 8.20 (d, 2H), 8.40 (d, 2H). Subsequent subjection of the product to general procedure E gave compound 65. Yield=77% (2 steps). TLC: Rf=0.32 (25% EtOAc/Hexane). 1H NMR (400 MHz, DMSO): δ1.55 (m, 1H), 1.80 (m, 1H), 4.70 (m, 1H), 4.80 (m, 1H), 5.10 (m, 1H), 5.80 (m, 1H), 7.40 (m, 3H), 7.45 (m, 6H), 7.55 (m, 6H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1[C:33]([C@@H:34]([OH:37])[CH2:35][NH2:36])=[CH:32][CH:31]=[C:30]([OH:38])[CH:29]=1>>[OH:37][CH:34]([C:33]1[CH:32]=[CH:31][C:30]([OH:38])=[CH:29][CH:28]=1)[CH2:35][NH:36][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)c1ccc(O)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccc(O)cc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and DL-octopamine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55–1.75 (m, 2 H), 2.00–2.15 (m, 2 H), 2.06 (s, 3 H), 2.50–3.20 (m, 5 H), 3.60–3.70 (m, 2 H), 4.80–4.90 (m, 1 H), 6.00 (brs, 1 H), 6.76 (d, J=9.7 Hz, 2 H), 6.80 (d, J=9.7 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 7.19 (d, J=8.7 Hz, 2 H), 7.59 (d, J=9.0 Hz, 2 H), 7.70 (d, J=8.7 Hz, 2 H), 9.47 (s, 1 H), 10.43 (s, 1 H); MS (ES) m/z: 525.3 (MH+); HRMS Calcd. for C27H33N4O5S (MH+): 525.2172. Found: 525.2178.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9].[Br-:16]>>[Br:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9]
Reactant: CCCCCNC(=O)NCCCCCO
Reactant: [Br-]
Product: CCCCCNC(=O)NCCCCCBr

Procedure:
Following the protocol described above, 1-(5-hydroxypentyl)-3-n-pentylurea (1.30 g, 6.02 mmol) was converted into the corresponding bromide (1.45 g, 87%), obtained as a colorless oil. TLC:EtOAc/hexanes (2:3), Rf˜0.40; 1H NMR (300 MHz) δ 4.44 (br s, —NH, 2H), 3.40 (t, J=6.7 Hz, 2H), 3.10-3.20 (m, 4H), 1.82-1.92 (m, 2H), 1.40-1.58 (m, 6H), 1.24-1.38 (m, 4H), 0.89 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz) δ 159.46, 40.02, 33.88, 33.02, 30.29, 29.92, 29.36, 25.83, 22.12, 14.02. HRMS calcd for C11H24BrN2O [M+1]+ 279.1072, found 279.1073.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][C:5]2[C:17]=1[C:16]([CH3:18])=[C:15]1[C:7](=[N:8][C:9]3[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=2.[C:22]([C:29]1NC=CN=1)([C:24]1[NH:25]C=C[N:28]=1)=O.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[C:3]([C:19]2[O:21][N:28]=[C:24]([CH2:22][CH3:29])[N:25]=2)=[N:4][C:5]2[C:17]=1[C:16]([CH3:18])=[C:15]1[C:7](=[N:8][C:9]3[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=2
Reactant: CC1=c2c(cc3c(c2C)-c2ccccc2N=3)N=C1C(=O)O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1noc(C2=Nc3cc4c(c(C)c3=C2C)-c2ccccc2N=4)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
3,4-Dimethylpyrrolo[2,3-b]carbazole-2-carboxylic acid (0.49 g, 1.76 mmol) and carbonyl diimidazole (0.33 g, 1.94 mmol) were dissolved in freshly distilled tetrahydrofuran (10 ml) in an oven-dried flask under a nitrogen atmosphere and this solution was stirred at room temperature for three hours. Meanwhile, in a second oven-dried flask, ethylamidoxime (0.39 g 4.43 mmol) was dissolved in THF (5 ml). To this was added crushed 3 Å sieves and the mixture was stirred at room temp for 45 min. Sodium hydride (60% dispersion in mineral oil, 0.142 g, 3.5 mmol) was added and the mixture stirred for a further 2.5 hours. The contents of the two flasks were combined (with further 10 ml THF) and stirred at room temp for 18 hours, by which time TLC showed complete consumption of the imidazolide intermediate. The solvent was removed in vacuo to give a yellow solid. Chromatography on silica (eluting with 25% ethyl acetate/hexane) gave the title compound as a yellow solid (0.150 g, 26%) with m.p. 258°-260° C. (decomp.). (Found: C, 72.03; H, 5.28; N, 16.42. C20H18N4O 0.08EtOAC requires: C, 72.33; H, 5.57; N, 16.60%); δH [2H6 ]-DMSO 11.55 (1H, s, 1-NH), 10.94 (1H, s, 9NH), 8.19 (1H, d, J 7.5, 5-H), 7.29-7.43 (2H, m, 7-H, 8-H), 7.22 (1H, s, 10-H), 7.13 (1H, ddd, J 8, 5.5, 2, 6-H), 3.20 and 3.03 (2×3H, 2×s, 3--CH3 and 4--CH3), 2.83 (2H, q, 7.5, CH2 CH3), 1.37 (3H, t, 7.5, CH2CH3); m/z (%) 330 (100, M+), 260 (34), 232 (29); νmax (KBr disk)/cm-1 3394, 1599, 1259.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24]O)=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2].C(N(CC)CC)C.CS([Cl:40])(=O)=O.[Cl-].[Li+]>ClCCl>[CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][Cl:40])=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Oc1cccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)Oc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a stirred solution of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-methanol (2.7 g, 7.08 mmol) in dichloromethane (14 mL) was added triethylamine (3.0 mL, 21.2 mmol) and methanesulphonyl chloride (1.24 mL, 15.6 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and lithium chloride (1.4 g, 33 mmol) was added at this temperature. The reaction mixture was stirred at room temperature for 15 hrs and diluted with dichloromethane (150 mL). The reaction mixture was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 1-(3-sec-butoxy-benzyl)-4-chloromethyl-6,7-dimethoxy-isoquinoline (2.1 g, 74% yield) as a brown oil. The crude product was used without further purification.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:33][CH:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28][CH2:29]2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: NC1CCN(c2ccccn2)CC1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Product: CC(C)N1C(=O)C(NC2CCN(c3ccccn3)CC2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-pyridin-2-ylpiperidine-4-amine dihydrochloride in a similar manner as described for Example 24 with TEA as base. 1H NMR (500 MHz CDCl3): δ 8.14 (dd, 1H), 7.58-7.53 (m, 2H), 7.48-7.41 (m, 4H), 6.62-6.55 (m, 2H), 5.23 (d, 1H), 4.42 (sept, 1H), 4.10-4.02 (m, 2H), 3.22-3.12 (m, 1H), 2.49-2.41 (m, 2H), 1.80-1.72 (m, 2H), 1.59 (d, 6H), 1.42-1.33 (m, 2H); 13C NMR (125 MHz CDCl3): 159.2, 158.7, 148.1, 137.7, 134.5, 131.9, 130.2, 128.9, 125.3, 113.6, 107.5, 106.9, 50.8, 47.8, 44.1, 32.1, 20.4; Mass Spectrum: M+H+ 427
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH2:9](N(CC)CC)[CH3:10]>C(OCC)(=O)C.BrCCBr>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH2:10][CH2:9]1
Reactant: CCN(CC)CC
Reactant: Nc1ccccc1S
Solvent: CCOC(C)=O
Solvent: BrCCBr
Product: c1ccc2c(c1)NCCS2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-aminothiophenol (5.01 g) in ethyl acetate (20 ml), 1,2-dibromoethane (4.14 ml) was added and stirred while heating at 60° C. under a nitrogen atmosphere. To the reaction mixture, triethylamine (9.72 ml) was added dropwise over 30 minutes and stirred at 60° C. for 10 hours. The reaction mixture was allowed to stand overnight at room temperature and then filtered to remove insoluble materials. The filtrate was washed sequentially with water and brine, dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 3:1) to give the titled compound, i.e., 3,4-dihydro-2H-1,4-benzothiazine (3.69 g) as a red-brown oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[N:11][C:10]([NH:13][C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)#[N:2].N[NH:24][C:25]([NH2:27])=[S:26].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[NH2:27][C:25]1[S:26][C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[N:12]=[N:11][C:10]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:8]=2)=[N:2][N:24]=1
Reactant: NNC(N)=S
Reactant: N#CCCCCc1ccc(NC(=O)Cc2ccccc2)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(CCCCc2ccc(NC(=O)Cc3ccccc3)nn2)s1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-phenylacetamide (14.7 g, 50.2 mmol) was charged into a 250 mL round bottom flask fitted with an open top reflux condenser. To the flask was added thiosemicarbazide (5.03 g, 55.2 mmol) and trifluoroacetic acid (88 mL). The reaction slurry was heated in a 65° C. bath for 2 h. After cooling to RT, H2O (150 mL) was added and stirred for 30 minutes. The mixture was then slowly transferred to a stirred 7.5% sodium bicarbonate solution (1400 mL) cooled in a 0° C. bath. The precipitate was collected by suction filtration, rinsed with water (2×200 mL), diethyl ether (2×200 mL) and dried under high vacuum overnight. The off-white solid was slurried in DMSO (200 mL) and heated in an 80° C. bath until the internal temperature reached 65° C. DMSO (105 mL) was used to rinse sides of flask. H2O (120 mL) was slowly added until the solution became slightly cloudy and then the mixture was removed from heat bath and allowed to cool to ambient temperature while stirring. The pale green precipitate was collected by suction filtration, rinsed with water (200 mL) and diethyl ether (2×200 mL). The solid was dried overnight under high vacuum to provide N-(6-(4-(5-amino-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)-2-phenylacetamide (1024, 15.01 g). 1H NMR (300 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.23 (d, J=8.916 Hz, 1H), 7.59 (d, J=8.826 Hz, 1H), 7.36 (m, 5H), 7.07 (s, 2H), 3.78 (s, 2H), 2.87 (t, J=6.799 Hz, 4H), 1.69 (bm, 4H)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:11]([CH2:14][CH2:15][NH2:16])([CH3:13])[CH3:12]>C(O)C>[CH3:12][N:11]([CH3:13])[CH2:14][CH2:15][NH:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Product: CN(C)CCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 61 %

Procedure:
A solution of 2-chloro-3-nitropyridine (1.76 g, 20.0 mmol) in ethanol is treated with Me2NCH2CH2NH2 (3.17 g, 20.0 mmol), stirred at ambient temperature for 17 h, heated to reflux temperature for 7 h, cooled to room temperature and concentrated in vacuo. The resulting solid residue is triturated with ethanol and suction filtered. The filtercake is air-dried to give the title compound as a yellow solid, 3.20 g (61% yield), mp 202-203° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]=1[C:16]#[N:17])=[O:4].S(=O)(=O)(O)[OH:19].C(=O)(O)[O-].[Na+]>>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]=1[C:16](=[O:19])[NH2:17])=[O:4]
Reactant: CNC(=O)Nc1snc(N2CCCC2)c1C#N
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CNC(=O)Nc1snc(N2CCCC2)c1C(N)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 10.5 g of 1-methyl-3-(4-cyano-3-(1-pyrrolidinyl)-5-isothiazolyl)urea and 15 ml of sulfuric acid was heated at 100° during 21/2 hours. The mixture was poured into 250 ml of stirred ice-water and neutralized by slow addition of saturated sodium bicarbonate solution. The separated solid was collected by filtration. The filtrate was allowed to stand for a short time, and filtered again. The collected solid was found to be a mixture of the desired product and unreacted starting material. A third solid that formed when the filtrate was allowed to stand overnight was isolated by filtration to give 4.6 g of 1-methyl-3-(4-carbamoyl-3-(1-pyrrolidinyl)-5-isothiazolyl)urea, which darkened at 241°, then decomposed at 257°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([N:26]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C3CCCCC3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclohexanecarbonyl chloride (48 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H39N3O3+H: 490, observed: 490.