Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:41](OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:51][CH2:50][CH2:49]1>>[O:22]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH2:20][N:16]1[C:14]1[CH:13]=[CH:12][C:11]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=3)[CH2:29][CH2:30]2)=[O:24])=[C:10]([C:9]([N:8]2[CH2:41][CH2:51][CH2:50][CH2:49]2)=[O:40])[CH:15]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: C1CCNC1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N3CCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzamide (202 mg) described in Example 785 and pyrrolidine (30 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (118 mg) was obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br)[CH2:2]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:10](=[O:19])[O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: COc1ccccc1B(O)O
Reactant: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Product: COc1ccccc1-c1ccccc1NC(=O)OC1CN2CCC1CC2
Yield: 72 %

Procedure:
Using general procedure E, quinuclidin-3-yl2-bromophenylcarbamate, 2-methoxyphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (102 mg, 72%). 1H NMR (500 MHz, CDCl3) δ 7.95 (br s, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.37 (t, J=7.5 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.72 (br s, 1H), 4.76 (m, 1H), 3.82 (s, 3H), 3.23 (m, 1H), 2.90-2.64 (m, 5H), 1.98-2.08 (m, 1H), 1.81-1.63 (m, 2H), 1.60-1.50 (m, 1H), 1.42-1.30 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 156.2, 153.8, 135.6, 132.1, 130.9, 129.7, 128.3, 127.1, 123.8, 121.5, 111.3, 71.8, 55.7, 55.5, 47.3, 46.5, 25.3, 24.5, 19.4 ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.48 min; (M+1) 353.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N+](C1C=C(S(O[CH2:23][C@@H:24]2[CH2:26][O:25]2)(=O)=O)C=CC=1)([O-])=O.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[O:25]1[CH2:26][C@H:24]1[CH2:23][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Yield: 114.8 %

Procedure:
Salicylaldehyde (486 mg, 3.99 mmol) and (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (900 mg, 3.47 mmol) was dissolved in DMF (5 ml) and Cs2CO3 (1.28 g, 3.94 mmol) was added. The reaction mixture stirred for 12 at room temperature. Water (100 ml) was added, and the mixture was extracted with DCM (2×50 ml). The combined organic extracts were washed with water (2×50 ml). The volatiles were removed in vacuo to give the subtitle compound (76%, 710 mg), which was used directly in the next step.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>C(Cl)Cl>[CH2:10]([NH:13][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: CCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CCCNC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Dry DCM (30 mL) was added to benzoyl chloride (2.06 mL, 17.7 mmol) followed by the dropwise addition of propylamine (3.19 mL, 38.9 mmol) over 5 min at 0° C. The system was stirred at 0° C. under nitrogen for 1 h and monitored by TLC. After 1 h the system was washed with 1M HCl (20 mL), brine (10 mL) and dried with MgSO4. The solvent was removed to give N-Propylbenzamide as a white solid (2.6 g, 15.9 mmol, 90%); Rf 0.38 (40:60 EtOAc:petrol). mp 87.6-88.9° C. Lit. 83-84° C.7 1H NMR: (300 MHz, CDCl3) δ 0.90 (t, 3H, J=7.4 Hz, CH2—CH2—CH3), 1.56 (sex, 2H, J=7.2 Hz, N—CH2—CH2), 3.33 (m, 2H, N—CH2), 6.21 (bs, 1H, NH), 7.31-7.43 (m, 3H, Ar—H), 7.69 (m, 2H, Ar—H). 13C NMR: (75 MHz, CDCl3) δ 11.8, 23.3, 42.1, 127.2, 128.8, 131.6, 135.2, 167.9. LC/MS-ES+ m/z 164.2 [MH+], 327.1, 328.1.
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.CN(C)P(N(C)C)N(C)C.O=C1[CH2:21][C@@H:20]([C@H:22]([N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])[C:23]([O:25][CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[O:19][NH:18]1.[Cl-].[Cl-].CN(C)P(N(C)C)N(C)C>O1CCCC1.C(OCC)(=O)C>[Cl:5][C:1]1[CH2:21][C@@H:20]([C@H:22]([N:39]2[C:40](=[O:49])[C:41]3=[CH:48][CH:47]=[CH:46][CH:45]=[C:42]3[C:43]2=[O:44])[C:23]([O:25][CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[O:19][N:18]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1C[C@@H]([C@@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)c3ccccc3C2=O)ON1
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@H]([C@@H]1CC(Cl)=NO1)N1C(=O)c2ccccc2C1=O
Reaction time: 0.03 h
Yield: 39.7 %

Procedure:
To 192 μl (2 mmole) of carbon tetrachloride in 25 ml of dry tetrahydrofuran under N2 at room temperature is added 310 μl (1.9 mmole) of hexamethylphosphorous triamide dropwise over one minute. Within two minutes 590 mg. (1.3 mmole) of (αS,5S)-oxo-α-phthalimido-5-isoxazolidine acetic acid, benzhydryl ester acid in approximately 5 ml of dry THF is added rapidly. The heterogeneous solution in stirred at 45° for 48 hours. Alternatively, to 590 mg. (1.3 mmole) of (αS,5S)-oxo-α-phthalimido-5-isoxolidine in 20 ml. of dry tetrahydrofuran under N2 at room temperature is added 610 mg. (2.6 mmole) of hexamethylphosphorous triamide dichloride (prepared by hexachloroethane in acetonitrile with hexamethylphosphorous triamide according to R. Appel and H. Scholer, Chem. Ber., 110, 2382 (1977)). The solution is refluxed for 48 hours. The reaction is taken up in 150 ml of ethyl acetate and washed with 50 ml of 0.1N hydrochloric acid followed by brine and then dried over sodium sulfate. After concentrating in vacuo the residue is chromatographed on 50 g of silica gel with 30% ethyl acetate hexane (200 ml elution) which yields 200 mg of crude product (33% yield), 245 mg of starting material (42%). The crude product yielded (α5,5S) 3-chloro-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid as needles, m.p. 178°-9° upon recrystallization from methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C@H:11]([CH3:27])[CH2:10]1.[Li][CH3:29]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])([CH3:29])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C@H:11]([CH3:27])[CH2:10]1
Reactant: CC(=O)c1ccc(S(=O)(=O)N2CCN(c3ccc(F)cc3F)C[C@H]2C)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc(F)cc2F)CCN1S(=O)(=O)c1ccc(C(C)(C)O)cc1
Yield: 73 %

Procedure:
To a solution of (R)-1-(4-(4-(2,4-difluorophenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)ethanone (220 mg, 0.558 mmol, prepared according to procedures similar to those described in Example 29A in THF (3 mL) was added MeLi (0.42 mL, 1.6 M in THF, 0.67 mmol) at −78° C. The resultant mixture was stirred for 6 h then quenched with aq. NH4Cl and aq. layer. It was extracted with DCM. The organic layer was dried over Na2SO4. The crude product was purified on SiO2 column eluted with hexanes/EtOAc to give the desired product as a white solid (167 mg, 73%). HRMS: calcd for C20H24F2N2O3S+H+, 411.15484. found (ESI-FTMS, [M+H]1+), 411.15477.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2CCO[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.C(N)C>>[C:1]([C:5]1[N:6]=[C:7]([NH:22][CH2:23][CH3:24])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CCN
Agent: Cl
Product: CCNc1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and ethanamine hydrochloride and isolated as white solid (1.1 mg, 7%). MS(m/e): 345.3 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(-c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: O=[N+]([O-])c1ccc(O)c(-c2ccccc2)c1
Reaction time: 3 h
Yield: 65.4 %

Procedure:
To a solution of 2-benzyloxy-5-nitro-biphenyl (81 mg, 0.27 mmol)) in 5 mL of methanol was added catalytic amount of 5% palladium on carbon under H2. The mixture was stirred under H2 for 3 hrs and filtered through celite. The filtrate was concentrated to give 2-hydroxy-5-nitro-biphenyl (38 mg).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([N:12]([CH2:20][CH:21]=[CH2:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[C:16]([O:15][C:13]([N:12]([CH2:20][CH:21]=[CH2:22])[C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:23])=[O:2])=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: C=CCN(C(=O)OC(C)(C)C)C(Cc1ccccc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 4 h

Procedure:
Combine (S)-2-[N-(t-butoxycarbonyl)-allylamino-3-phenyl-propionic acid methyl ester (0.32 g, 1.0 mmol) and 1M sodium hydroxide (10 mL, 10 mmol) in ethanol (10 mL). Stir for 4 hours. Acidify the reaction mixture with 1M hydrochloric acid and extract with ethyl acetate. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel eluting with 3% methanol/dichloromethane to give the title compound: TLC Rf =0.40 (silica gel, 5% methanol/dichloromethane).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[C:40]([NH:42][CH3:43])=[O:41]>C(#N)CC.CS(C)=O>[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[N:47]1[CH2:48][CH2:49][N:50]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:51][CH2:52]1)[C:40]([NH:42][CH3:43])=[O:41]
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(Cl)c1
Temperature: 90 °C
Yield: 28.7 %

Procedure:
To a suspension of (S)-3-((S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (111 mg, 0.476 mmol) in propiononitrile (1.2 mL) was added (cyanomethyl)trimethylphosphonium iodide (139 mg, 0.571 mmol) and DIEA (249 μl, 1.428 mmol) and finally 3-chloro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (138 mg, 0.476 mmol). The vial was heated to 90° C. for 16 hours. The crude r×n was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic). The fractions were collected, concentrated until a precipitate was visible and filtered. The solids were washed with water and collected to retrieve the product as a white solid (64 mg, 29% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (br. s., 1H), 8.43 (d, J=4.3 Hz, 1H), 7.87 (s, 1H), 7.76 (dd, J=8.3, 1.5 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.54-7.74 (m, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.99 (br. s., 1H), 4.52 (d, J=12.6 Hz, 1H), 3.85 (br. s., 1H), 3.44 (br. s., 2H), 2.92 (d, J=4.5 Hz, 4H), 2.75 (d, J=4.5 Hz, 4H), 2.52-2.69 (m, 3H), 1.99-2.09 (m, 1H), 1.85 (d, J=12.4 Hz, 1H), 1.64 (d, J=12.4 Hz, 1H), 1.32-1.58 (m, 3H). [M+H] calc'd for C24H29ClN6O2, 469; found, 469.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:13]1[O:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>C(O)(C)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:13]([OH:15])[CH2:14][NH:28][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCN
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Solvent: CC(C)O
Product: CC(C)CCNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of N-benzyloxycarbonyl 3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (30.1 g, 0.10 mol) and 165 mL of isoamylamine in 150 mL of isopropyl alcohol was heated to reflux for 2.5 hours. The solution was cooled to room temperature, concentrated in vacuo and then recrystallized. The product was isolated by filtration and from ethyl acetate/hexane to afford 31.7 g (81%) of N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]N-isoamylamine.
Reaction SMILES: Cl.[NH:2]([C:4]1[S:5][C:6]2[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=2[N:8]=1)[NH2:3].CC[O-].[Na+].[Na].[C:18](#[N:22])/[CH:19]=[CH:20]/[CH3:21]>O.C(O)C>[NH2:22][C:18]1[CH2:19][CH:20]([CH3:21])[N:2]([C:4]2[S:5][C:6]3[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=3[N:8]=2)[N:3]=1
Reactant: NNc1nc2c(s1)CCCC2
Reactant: C/C=C/C#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1CC(N)=NN1c1nc2c(s1)CCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
20 g of 2-hydrazino-4,5,6,7-tetrahyro-benzothiazole hydrochloride are added to a sodium ethylate solution of 5.7 g of sodium and 250 ml of ethanol and the mixture is stirred at room temperature for 10 minutes. 5.5 g of crotononitrile are then added dropwise and the mixture is boiled under reflux for 5 hours. After cooling, the ethanol is stripped off in vacuo and the residue is taken up in water. The insoluble material is filtered off and washed thoroughly with water, acetone and ether in succession. After drying, 11.8 g of beige crystals of 3-amino-5-methyl-1-(4,5,6,7-tetrahydro-benzothiazolyl)-2-pyrazoline of melting point 247°-249° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:18][CH:19]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CN)cc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CNS(C)(=O)=O)cc2)n1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of [6-(4-aminomethyl-phenyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (5.7 g 19 mmol) and Et3N (2.88 g, 29 mmol) in dichloromethane (50 mL) was added dropwise MsCl (2.7 g, 19 mmol) at 0° C. The reaction mixture was stirred at this temperature for 30 min, and then washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was recrystallized with DCM/Petroleum Ether (1:3) to give {6-[4-(methanesulfonylamino-methyl)-phenyl]-pyridin-2-yl}carbamic acid tert-butyl ester (4.0 g, 44% over two steps). 1H NMR (300 MHz, CDCl3) δ 7.90-7.97 (m, 3H), 7.75 (t, J=8.4, 8.4 Hz, 1H), 7.54-7.59 (m, 1H), 7.38-7.44 (m, 3H), 4.73 (br, 1H), 4.37 (d, J=6.0 Hz, 2H), 2.90 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)=[O:18].O.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CN1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Diisopropylethylamine (6.2 mL, 36.0 mmol) and pyrrolidine (2.3 mL, 27.6 mmol) were added to a THF (90 mL) solution of 2-bromo-1-(4-bromophenyl)ethanone (5.0 g, 18.0 mmol), and stirred at room temperature for 2 hours. Saturated sodium bicarbonate water was added to the reaction liquid, extracted with chloroform, and dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (C-200, methanol:chloroform=1:99 to 3:97) to obtain the entitled compound (2.35 g, 49%).
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Cl:43][C:44]1[CH:53]=[C:52]2[C:47]([CH:48]=[C:49]([NH2:54])[N:50]=[CH:51]2)=[CH:46][CH:45]=1.Cl[C:56]1[CH:61]=[C:60]([CH2:62][N:63]2[CH2:67][CH2:66][CH2:65][CH2:64]2)[CH:59]=[CH:58][N:57]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[Cl:43][C:44]1[CH:53]=[C:52]2[C:47]([CH:48]=[C:49]([NH:54][C:58]3[CH:59]=[C:60]([CH2:62][N:63]4[CH2:64][CH2:65][CH2:66][CH2:67]4)[CH:61]=[CH:56][N:57]=3)[N:50]=[CH:51]2)=[CH:46][CH:45]=1
Reactant: Clc1cc(CN2CCCC2)ccn1
Reactant: Nc1cc2ccc(Cl)cc2cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Clc1ccc2cc(Nc3cc(CN4CCCC4)ccn3)ncc2c1
Yield: 31.6 %

Procedure:
Pd2(dba)3(102 mmg, 0.11 mmol) and xantphos (92 mg, 0.16 mmol) were added to a solution of 7-chloroisoquinolin-3-amine (200 mg, 1.12 mmol) (Preparation C-9), 2-chloro-4-pyrrolidin-1-ylmethyl-pyridine (220 mmg, 1.12 mmol) (Preparation B-11) and Cs2CO3 (500 mg, 1.53 mmol) in toluene (50 mL). The suspension was heated under reflux overnight, and THF (50 mL) was added in to dilute the mixture. After filtration, the filtrate was concentrated. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1/1) and afforded the title compound (120 mg, 32% yield) as a yellow solid.
Reaction SMILES: [O:1]1[CH:8]([CH3:9])[CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(=O)(=O)(O)O.[CH:15]([OH:18])([CH3:17])[CH3:16]>>[CH:15]([O:18][CH:8]([CH3:9])[CH:2]([OH:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:17])[CH3:16]
Reactant: CC(C)O
Reactant: CCOC(=O)C1OC1C
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(O)C(C)OC(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
That is, to ethyl 2,3-epoxybutanoate (13.0 g, 0.1 mol) dissolved in isopropanol (30 ml) was added sulfuric acid (0.5 ml), and the mixture was stirred at 60° C. for 5 hours. Subsequently, excessive isopropanol was removed under reduced pressure to obtain ethyl 3-(isopropoxy)-2-hydroxybutanoate. The product obtained and p-toluenesulfonyl chloride (20.9 g, 0.11 mol) were added to pyridine (50 ml), and the mixture was stirred at room temperature for 5 hours. Subsequently, water was added to the reaction mixture, and the oily product liberated was extracted with toluene. After the toluene layer was washed with water and dried over sodium sulfate, toluene was removed under reduced pressure. The oily product obtained was isolated by silica gel column chromatography (Wako gel C-200 (trade name, produced by Wako Junyaku K.K.), eluted by hexane: ethyl acetate=9:1) to obtain ethyl 3-(isopropoxy)-2-p-toluenesulfonyloxybutanoate (27.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>O1CCCC1.O>[C:17]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1C
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
A solution of ethyl 5-hydroxy-1-methyl-1H-indole-2-carboxylate (2.2 g, 10.0 mmol) in 50 mL of tetrahydrofuran is treated dropwise with acetyl chloride (0.80 mL, 0.88 g, 11.3 mmol) followed by triethylamine (1.6 mL, 1.2 g, 11.5 mmol). The mixture is stirred at room temperature for 16 hours, then diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (anhydrous magnesium sulfate), and evaporated. Recrystallization of the residue from ether-pentane gives 2.0 g (77%) of product; mp 87°-89° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[N:10][C:11]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:12][CH:13]=1
Reactant: C1CCNCC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Brc1cnc(N2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Piperidine (5.1 ml, 51.6 mmol) was added to a stirred solution of 5-bromo-2-chloropyrimidine (5 g, 25.8 mmol) and triethylamine (9.0 ml, 64.5 mmol) in toluene (30 ml). After stirring at room temperature for 24 hours the reaction mixture was diluted with ethyl acetate and washed with 2N hydrochloric acid, brine and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with ethyl acetate to afford the title compound (D32).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[OH:14]O.O>C(O)(=O)C.OS(O)(=O)=O>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]2[C:4]([O:12][C:5](=[O:14])[NH:6][C:7]2=[CH:8][CH:9]=1)=[O:13]
Reactant: OO
Reactant: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2ccc(Cl)c(Cl)c2c(=O)o1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 89.6 %

Procedure:
To a suspension of 4,5-dichloroisatin (13f, 216 mg, 1.0 mmol) in glacial acetic acid (5 mL) and 2 drops (about 0.02 mL) of conc H2SO4 was added 0.34 mL (about 3 mmol) of 30% H2O2. The mixture was stirred at 70° C. (bath) for 2.5 h (the mixture turned into a solution, then formed a precipitate), allowed to cool to 22° C. and cold water (10 mL) was added. The precipitate was filtered, washed with water (6×10 mL), dried to give 208 mg (90%) of 14e as an orange-yellow powder, mp 267°-9° C. (dec). IR, 1810, 1779, 1762, 1711, 1600, 1335, 1254, 1041, 1024 cm-1 ; 1H NMR δ 11.952 (bs, 1H), 7.928 (d, J=8.7 Hz, 1H), 7.110 (d, J=8.7Hz, 1H); HRMS Calcd for C8H3Cl2NO3 : 230.9490; Found: 230.9489.