Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH:38]=[O:39])[S:36][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:33]4[CH:34]=[C:35]([CH:38]=[O:39])[S:36][CH:37]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Temperature: 150 °C
Yield: 89.2 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (909 mg, 2.2 mmol) in dioxane (7.5 mL) and H2O (2.5 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (1.57 g, 6.6 mmol), potassium carbonate (1.82 g, 13.2 mmol), and tetrakis(triphenylphospine)palladium (0) (30 mg, 0.22 mmol). The reaction was heated in the microwave at 150° C. for 20 min. The mixture was then concentrated to dryness. EtOAc (50 mL) was added to the residue and washed with brine. The precipitate which formed between the water and organic layer was filtered and collected as a brown solid to give 874 mg of the title compound (89%).
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].S(Cl)([Cl:33])=O.[CH:35](O)([CH3:37])[CH3:36]>>[N:1]#[N:2].[ClH:33].[ClH:33].[CH:35]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])([CH3:37])[CH3:36]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: CC(C)O
Reactant: O=S(Cl)Cl
Agent: N#N
Product: CC(C)OC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To an ice-cooled suspension of 1.0 gram of N2 -dansyl-L-arginine in 15 ml of isopropanol was added dropwise 0.5 ml of thionyl chloride with vigorous stirring. After being allowed to stand for 2 hours at room temperature, the reaction mixture was refluxed for 4 hours, and was evaporated to dryness (syrup). Treatment of the residual syrup with cold ethyl ether gave crude crystals. After recrystallization from isopropanol-ethyl ether, colorless N2 -dansyl-L-arginine isopropyl ester dihydrochloride was obtained in 90% yield; mp. 110°-120°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[ClH:10].Br[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Br>ClC1C=CC=CC=1.C(OCC)C>[ClH:10].[ClH:10].[F:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: BrCCNCCBr
Reactant: Nc1ccc(F)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: Clc1ccccc1
Product: Fc1ccc(N2CCNCC2)cc1F
Temperature: 25 °C
Yield: 201.2 %

Procedure:
A mixture of 3,4-difluoroaniline (3.6 g) and bis(2-bromoethyl)amine hydrochloride (5.0 g) in 50 mL of chlorobenzene is warmed to reflux under argon for 48 hours. The mixture is cooled to room temperature, diluted with 100 mL of diethyl ether, and extracted with three 150 mL portions of 1N HCl. The aqueous extracts are backwashed with three 50 mL portions of ether, which are discarded. The combined aqueous fractions are basified to pH 11 with 12N NaOH. The resulting mixture is extracted with three 50 mL portions of methylene chloride, and the combined organic extracts are dried over sodium sulfate. The solvent is removed under reduced pressure, and the resulting residue is taken up in 50 mL of diethyl ether and filtered through Celite. The resulting solution is treated with a 1 M ethereal HCl solution (56 mL), and the resulting precipitate is collected and dried under vacuum to give 5.1 g of the title compound, mp 100-104° C. (decomposes). ##STR7## Preparation of 2-[4-(3,4-difluoro-phenyl)-piperazin-1-ylmethyl]-quinoline
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[N:27]=[C:26]4[CH2:29][CH2:30][CH2:31][CH:32]5[CH2:37][C:36](=[O:38])[CH2:35][CH2:34][C:33]5([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[C:25]4=[CH:24][C:23]=3[CH:22]=[N:21]2)=[CH:16][CH:15]=1>C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[N:27]=[C:26]4[CH2:29][CH2:30][CH2:31][CH:32]5[CH2:37][C:36]6([CH2:8][O:38]6)[CH2:35][CH2:34][C:33]5([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[C:25]4=[CH:24][C:23]=3[CH:22]=[N:21]2)=[CH:16][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1CCC2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4nc3CCCC2C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(-n2ncc3cc4c(nc32)CCCC2CC3(CCC42Cc2ccccn2)CO3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
Sodium hydride (60 wt % in oil, 0.454 g, 11.35 mmol) and DMSO (25 mL) were heated to about 65° C. for about 30 min then cooled to rt. THF (50 mL) was added then the mixture was cooled to about 0° C. Trimethylsulfoxonium iodide (2.56 g, 11.63 mmol) was added then after about 30 min rac-(4aR,12bR)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-3 (2H)-one (118, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (2.5 g, 5.68 mmol) was added. The mixture was allowed to warm to rt and stir for about 12 h. The mixture was concentrated under reduced pressure then the material was partitioned between water (100 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (25 mL) then the organic solutions were combined and washed with water (75 mL) then brine (30 mL), dried over MgSO4 then filtered. The filtrate was concentrated under reduced pressure and the material was purified on silica gel (120 g) using a gradient from 0-10% MeOH in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(2′R,4aS,12bS)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine-3,2′-oxirane] (119, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (1.865 g, 72.3%); LC/MS, method 3, Rt=2.65 min, MS m/z 455 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.42-8.34 (m, 2H), 8.32-8.28 (m, 1H), 8.20 (s, 1H), 7.75-7.72 (m, 1H), 7.49-7.37 (m, 3H), 7.06 (ddd, J=5.2, 4.5, 0.9 Hz, 1H), 6.72-6.67 (m, 1H), 3.73 (d, J=12.8 Hz, 1H), 3.59-3.47 (m, 1H), 3.42-3.33 (m, 1H), 3.02 (d, J=12.9 Hz, 1H), 2.70-2.56 (m, 1H), 2.44-2.34 (m, 2H), 2.13-2.00 (m, 1H), 1.96-1.81 (m, 2H), 1.79-1.58 (m, 3H), 1.35-1.21 (m, 3H), 1.21-1.10 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]=O)=[CH:4][CH:3]=1.[ClH:12].Cl.[NH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:27]=2[CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:30]=1)(=[O:20])=[O:19].CCN(CC)CC.[BH4-].[Na+]>CO>[ClH:1].[ClH:12].[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[C:22]3[CH:23]=[CH:24][N:25]=[CH:26][C:27]=3[CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Reactant: O=CCOc1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=S(=O)(NCCNCCOc1ccc(Cl)cc1)c1cc(-c2ccccc2)cc2cnccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A 1.96 mL of (4-chloro-phenoxy)-acetaldehyde stock solution (˜0.46 mmol) is added to a stirred mixture of 7-phenyl-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide di-hydrochloride (152 mg, 0.380 mmol), 4 Å molecular sieve (300 mg) and NEt3 (0.212 mL, 1.52 mmol) in anhydrous CH3OH (4 mL) at ambient temperature under nitrogen. The resultant mixture is stirred for 16 hours. Then the mixture is cooled to 0° C. before it is treated with powdered sodium borohydride (43.1 mg, 1.14 mmol). The mixture is stirred at 0° C. for 1 hour, then at ambient temperature for another 1 hour. After filtration and subsequent concentration in vacuo, the crude product is chromatographed on silica (gradient 5-25% CH3OH in EtOAc) to give 104 mg of the free amine product as a gum (0.216 mmol, 57% yield). The free amine (102 mg, 0.212 mmol) is dissolved in EtOAc (15 mL) and treated dropwise with 1N HCl/Et2O solution (0.635 mL) with stirring under nitrogen. The white suspension is stirred for 15 minutes, filtered and dried under vacuum at 60° C. to give 112 mg (0.202 mmol, 95% yield) of the title compound as a white powder. ESIMS: m/z 482 [(M+H)+, 35Cl], 484 [(M+H)+, 37Cl].
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][C@H:4]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:49][C@@H:50]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[CH:61][CH:60]=1)[C:51]([NH:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>CN(C=O)C.C(OCC)C>[CH2:66]([O:65][C:62]1[CH:63]=[CH:64][C:59]([CH2:58][CH:50]([NH:49][C:5](=[O:7])[CH:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:3][CH:2]([CH3:1])[CH3:14])[C:51](=[O:52])[NH:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[CH:60][CH:61]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
(S)-4-Methyl-2-morpholin-4-yl-pentanoic acid (0.161 g, 0.800 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added in succession N,N-diisopropyl-ethylamine (0.420 mL, 2.41 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.303 g, 0.799 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes, solid (S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (0.290 g, 0.800 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 45 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether. The resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo, trituration with ether and drying under vacuum provided 0.27 g (62%) of the pure titled compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]2=[O:23])[CH2:2]1.Br[CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:38][CH3:39])[C:33]=2[CH3:37])[CH:28]=1>>[CH3:37][C:33]1[C:32]([O:38][CH3:39])=[CH:31][CH:30]=[C:29]2[C:34]=1[CH:35]=[CH:36][C:27]([CH2:26][CH2:25][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=4)[C:10]3=[O:23])[CH2:2]1)=[CH:28]2
Reactant: COc1ccc2cc(CCBr)ccc2c1C
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCCNC1)CC2
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCCN(CCc3ccc4c(C)c(OC)ccc4c3)C1)CC2

Procedure:
Prepared from 2-[(hexahydro-azepin-3-yl)-methyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 2-(2-bromoethyl)-5-methyl-6-methoxy-naphthalene analogously to Example 1.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C:16]([OH:18])=[O:17])=[O:5])[CH3:2].Cl.[CH3:22]O>>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C:16]([O:18][CH3:22])=[O:17])=[O:5])[CH3:20]
Reactant: CCN(CC)C(=O)c1cccc2c(CC(=O)O)c[nH]c12
Reactant: CO
Agent: Cl
Product: CCN(CC)C(=O)c1cccc2c(CC(=O)OC)c[nH]c12
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of (7-((diethylamino)carbonyl)-1H-indol-3-yl)acetic acid (2.38 g, 8.68 mmol) in methanol (10 mL) is added a 10% hydrogen chloride solution in methanol (30 mL) under nitrogen atmosphere, and the mixture is refluxed for 30 minutes. The reaction solution is cooled to room temperature, and the solvent is distilled off. To the residue is added chloroform, and the mixture is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation, and the resultant crude product is purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→ethyl acetate) to give methyl (7-((diethylamino)carbonyl)-1H-indol-3-yl)acetate (1.93 g, yield: 77%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)=O.C(C1(C(OC)=O)CCC1)=O>>[O:22]1[CH2:23][CH2:24][CH:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:3][CH2:2][N:1]([CH2:25][C@H:27]5[CH2:28][CH2:29][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:31][CH2:32]5)[CH2:6][CH2:5]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reactant: c1cc(OC2CCOCC2)c2c(OCC3CCNCC3)noc2c1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)[C@H]1CC[C@H](CN2CCC(COc3noc4cccc(OC5CCOCC5)c34)CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 3-(piperidin-4-ylmethoxy)-4-(tetrahydro-2H-pyran-4-yloxy)-1,2-benzisoxazole (EXAMPLE 27, Step 1) and methyl trans-4-formylcyclohexanecarboxylate (JP 49-48639) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[Li][CH3:10]>C1(C)C=CC=CC=1>[CH3:10][C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][N:1]=1
Reactant: Cc1cncc(C)c1
Reactant: [Li]C
Solvent: Cc1ccccc1
Product: Cc1cnc(C)c(C)c1
Yield: 72.7 %

Procedure:
To a solution of 3,5-lutidine (42.86, 0.400 mol) in toluene (240 ml) in a three-neck flask, under N2 atmosphere, was added dropwise MeLi [0.33M in ether, 1330 ml (0.44 mol), prepared from CH3I and Li or obtained from Aldrich]. The reaction was stirred and heated at 60°-80° C. for 6 h, after which time the ether was distilled off. The remaining solution was poured into water/crushed ice (200 ml), acidified with conc. HCl and extracted with ethyl acetate (2×100 ml). The aqueous solution then was basified with aq. NaOH and extracted with CH2Cl2 (3×100 ml). The CH2Cl2 extracts were combined, washed with sat. NaCl solution (1×50 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was distilled under reduced pressure to give 2,3,5-trimethylpyridine (35.24 g, 72%) as a pale oil; bp 65°-71° C./11 mmHg. A solution of 2,3,5-trimethylpyridine (36.35 g, 0.30 mol) in AcOH (120 ml) was treated with 30% H2O (45 ml) and the mixture heated at 100° C. for 3 h. An additional aliquot of 30% H2O2 (15 ml) was added and the mixture was heated for an additional 10 h at 100° C. The reaction was cooled to rt, diluted with water (100 ml) and concentrated in vacuo. The residue again was diluted with water (200 ml), neutralized with KOH pellets and extracted with CH2Cl2 (3×100 ml). The extracts were combined, washed with sat. NaCl (1×50 ml), dried (MgSO4) and the solvent removed in vacuo to give 2,3,5-trimethylpyridine-N-oxide as a pale yellow solid, (50 g, quant.); mp 41°-42° C. (hexanes, colorless needles).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1.[CH2:15]1[N:20]2[CH2:21][N:22]3[CH2:24][N:18]([CH2:19]2)[CH2:17][N:16]1[CH2:23]3>C(Cl)(Cl)Cl>[Br-:1].[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N+:16]23[CH2:17][N:18]4[CH2:24][N:22]([CH2:21][N:20]([CH2:19]4)[CH2:15]2)[CH2:23]3)=[CH:4][CH:5]=1)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)c1ccc(C[N+]23CN4CN(CN(C4)C2)C3)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
An ice solution of 127.5 g. (0.5 mole) of α-bromo-4-pivaloyl toluene in 600 ml. of chloroform is added dropwise to 77.0 g. (0.55 mole) of hexamethylene tetramine in 550 ml. chloroform. The resulting mixture is stirred for 2 days at room temperature and the solvent evaporated in vacuo. The residue is treated with ether and the resulting solid filtered and washed thoroughly with ether to give a white solid, 1-(4-pivaloylbenzyl)-3,5,7-triaza-1-azonia-adamantane bromide. The resulting solid is suspended in 300 ml. of 6N hydrochloric acid and steam distilled until no more formaldehyde is evolved. The distillation residue is poured onto ice and 180 ml. of 50% sodium hydroxide. The basic solution is extracted with ether and the ether is washed with water, brine and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is dissolved in ethanol and treated with ether/hydrochloric acid to give 4-pivaloyl benzylamine hydrochloride, m.p. 222° C. to 225° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH:25](OCC)=[O:26]>C(O)C>[CH:25]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: CCOC=O
Reactant: NCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Solvent: CCO
Product: O=CNCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1

Procedure:
A mixture of phenylmethyl [2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]carbamate (0.25 g), ethyl formate (5 ml) and ethanol (1 ml) was heated under reflux for 9 h. The solvent was evaporated in vacuo and the residue was evaporated with ethanol (2×5 ml) to give the title compound (0.27 g) as cream crystals m.p. 114°-6°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([Cl:18])[C:7]([CH3:17])=[C:8]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=2)[C:4](=[O:19])[C:3]21[CH2:23][CH2:22][CH2:21][CH2:20]2.[OH-].[K+].CO.Cl>O>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([Cl:18])[C:7]([CH3:17])=[C:8]([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=2)[C:4](=[O:19])[C:3]21[CH2:23][CH2:22][CH2:21][CH2:20]2
Reactant: COC(=O)COc1cc2c(c(Cl)c1C)C(=O)C1(CCCC1)C2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(OCC(=O)O)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O

Procedure:
A mixture of methyl [1' ,3'-dioxo-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-yloxy]acetate (3.5 g., 0.0104 mole) potassium hydroxide (0.67 g., 0.012 mole) and methanol (200 ml.) is refluxed for 1/2 hour, diluted with water (800 ml.) and acidified with hydrochloric acid affording 3.1 g. of [1' ,3'-dioxo-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-yloxy]acetic acid which melts at 204°-5°C. after recrystallization from acetic acid-water.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:25])[CH2:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)=[CH:4][CH:3]=1.[Sn](Cl)Cl>C(OCC)(=O)C.CO.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1/[CH:14]=[CH:13]/[C:12](=[O:24])[CH2:11][C:10](=[O:25])/[CH:9]=[CH:8]/[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1ccccc1/C=C/C(=O)CC(=O)/C=C/c1ccc(O)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 46.5 %

Procedure:
To a solution of (1E,6E)-1-(4-hydroxyphenyl)-7-(2-nitrophenyl)hepta-1,6-diene-3,5-dione (26 mg, 77 μmol, synthesized in Example 344) in 3.0 mL of ethyl acetate was added anhydrous tin(II) chloride (57 mg, 0.30 mmol) at room temperature. After being stirred at 60° C. for 1.5 h, the reaction mixture was cooled to room temperature, and was diluted with 10% methanol/chloroform and saturated NaHCO3 aqueous solution, successively. The mixture was shaken before filtration to remove inorganic salts. The organic layer after separation was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 60/40) to obtain the title compound as a solid (11.0 mg, 46%) having the following characteristics.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@H:16]([CH3:17])[CH2:15][C@@H:14]([CH2:18][C:19](O)=[O:20])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C@H:16]([CH3:17])[CH2:15][C@@H:14]([CH2:18][C:19](=[O:20])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1
Reactant: C[C@@H]1C[C@@H](CC(=O)O)n2c(=O)c(=O)[nH]c3cc(Br)cc1c32
Product: C[C@@H]1C[C@@H](CC(=O)Nc2ccccc2)n2c(=O)c(=O)[nH]c3cc(Br)cc1c32
Yield: 87.9 %

Procedure:
A procedure similar to that described in Example 5 was carried out with trans-9-bromo-5-carboxymethyl-7-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (90 mg, 0.255 mmol) and aniline (25 μL, 0.28 mmol) to give 96 mg of the title compound (88%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ12.09 (bs, 1H), 7.56 (d, 2H, J=7.3 Hz), 7.32 (d, 1H, J=2 Hz), 7.30 (t, 2H, J=7.3 Hz), 7.21 (d, 1H, J=2 Hz), 7.05 (t, 1H, J=7.3 Hz), 5.15~5.25 (m, 1H), 3.19 (ddq, 1H, J=12.5, 4.6, 6.6 Hz), 2.55~2.70 (m, 2H), 2.13 (ddd, 1H, J=14.2, 4.6, 2.3 Hz), 1.67 (ddd, 1H, J=14.2, 12.5, 4.9 Hz), 1.33 (d, 3H, J=6.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH2:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1>CN(C=O)C>[ClH:1].[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:16]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]2=[NH:10])=[CH:6][CH:7]=1
Reactant: Nc1ncccn1
Reactant: ClCc1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: Cl
Product: N=c1ncccn1Cc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
300 mg (1.86 mmol) of 2-chloro-5-chloromethyl pyridine was dissolved in 6 ml of anhydrous DMF, 118 mg (1.24 mmol) of 2-aminopyrimidine was added thereto, and the resulting mixture was stirred at 80° C. for 8 hours. After the reaction was completed, the reaction solution was returned to room temperature to distill off DMF under reduced pressure. Diethyl ether was added thereto, and thus crystallization was occurred on the wall surface of an eggplant flask. Diethyl ether was removed by decantation and dried well to obtain 1-((6-chloropyridin-3-yl)methyl)pyrimidin-2(1H)-imine hydrochloride. Amount obtained 107 mg (yield 34%)