Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([C:27]([OH:29])=O)[CH2:22]2)=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[NH2:35][CH2:36][CH2:37][OH:38]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([C:27](=[O:29])[NH:35][CH2:36][CH2:37][OH:38])[CH2:22]2)[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: NCCO
Reactant: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)NCCO)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 59.6 %

Procedure:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-2-carboxylic acid (0.5 g, 0.9 mmol) was reacted with 2-aminoethanol (72 mg, 1.2 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.32 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH:13]=[CH:12][N:11]([N:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[S:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][B-:24]([F:27])([F:26])[F:25].[CH3:28][O+](C)C>ClCCl>[F:23][B-:24]([F:27])([F:26])[F:25].[CH:15](=[N:14][N+:11]1[CH:12]=[CH:13][N:9]([N:8]=[CH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[S:22][CH3:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=c1n(N=Cc2ccccc2)ccn1N=Cc1ccccc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CSc1n(N=Cc2ccccc2)cc[n+]1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.06 g of 1,3-bis(benzylideneamino)-1,3-dihydro-2H-imidazole-2-thione in 100 ml of absolute dichloromethane are treated with 1.47 g of trimethyloxonium tetrafluoroborate, the mixture is stirred at room temperature for 3 hours and the resulting precipitate is removed by filtration under suction. From the filtrate, there is precipitated by the addition of diethyl ether an additional portion of the desired product which, together with the first portion, is washed once with water, once with cold methanol and three times with diethyl ether and subsequently re-precipitated from acetonitrile/diethyl ether. There is obtained colorless 1,3-bis(benzylideneamino)-2-(methylthio)imidazolium tetrafluoroborate of melting point 215°-220° (decomposition).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:25]([CH2:23][CH3:24])[C:26]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=O
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Yield: 77.8 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (380 mg, 9.52 mmol) with ethyl isocyanate (2.0 mL, 25.36 mmol) in DMA afforded 1.725 g of the title compound as a solid, mp 156-157° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH3:20])=[CH:5][CH:4]=[N:3]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]=1[CH3:32].C(N(CC)CC)C>C1COCC1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[CH3:20])=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)=[O:28])=[CH:25][C:24]=1[CH3:32]
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CN1CCCC1COc1ccc(N)cc1-c1ccnn1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(OC[C@@H]3CCCN3C)c(-c3ccnn3C)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
A mixture of 3-(2-Methyl-2H-pyrazol-3-yl)-4-(1-methyl-pyrrolidin-2-ylmethoxy)-phenylamine (64 mg, 0.23 mmole), 4-fluoro-3-methyl-benzoyl chloride (60 mg, 0.35 mmole), and triethylamine (63.4 μL, 0.46 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 92 mg, 95% yield). Exact mass calculated for C24H27FN4O2 422.2, found 423.2 (MH+).
Reaction SMILES: [CH2:1]([S:6](Cl)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1>N1C=CC=CC=1.ClCCl>[F:34][C:31]([F:32])([F:33])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:15]=[CH:16][C:11]([NH:10][S:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[CH:12][CH:13]=2)[CH2:22][CH2:21]1)=[O:24]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Reactant: CCCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCS(=O)(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4 %

Procedure:
1-Pentanesulfonyl chloride (0.034 g, 0.30 mmol) was added slowly to a solution of [4-(5-aminopyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone in pyridine (2 mL) at 0° C. The mixture was stirred at 25° C. for 16 hours and then diluted with dichloromethane. The organic phase was washed with water and saturated NaCl solution, dried over anhydrous MgSO4. After removal of dichloromethane, the product was purified by column chromatography to afford the title compound in 4% yield (2.7 mg). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.87, 7.74, 7.61, 7.36, 6.94, 4.47, 4.11, 3.87, 3.68, 3.60, 3.42, 2.99, 1.77, 1.32, 0.88. MS (ES+) m/z 485.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20]C4CCCCO4)[C:12](=[O:27])[N:11]([CH2:28][CH2:29][CH2:30][O:31]C4CCCCO4)[C:10]=3[O:9][C:8]=2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:27])[N:11]([CH2:28][CH2:29][CH2:30][OH:31])[C:10]=3[O:9][C:8]=2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)=[CH:45][CH:46]=1
Reactant: O=c1c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc2n(CCCOC2CCCCO2)c(=O)n1CCCOC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc2n(CCCO)c(=O)n1CCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1,3-bis(3-(tetrahydro-2H-pyran-2-yl oxy) propyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (67 mg, 0.1 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction was stirred at RT for 1 h then concentrated to a residue which was diluted with EA (10 mL) and water (2 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1,3-bis(3-hydroxypropyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (29 mg, 58% yield) as an oil. 1H NMR (DMSO-d6) δ: 7.61 (s, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.28 (s, 4H), 4.35 (s, 2H), 4.29 (t, J=6.9 Hz, 2H), 4.09 (t, J=7.1 Hz, 2H), 3.71 (t, J=5.9 Hz, 2H), 3.62 (t, J=6.3 Hz, 2H), 2.16-2.02 (m, 2H), 1.94-1.80 (m, 2H). LCMS: MH+ 503 and TR=2.826 min.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[NH:59][CH2:58][CH2:57][CH2:56]2>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:59]2[C:60]3[C:55](=[CH:54][C:53]([F:52])=[CH:62][CH:61]=3)[CH2:56][CH2:57][CH2:58]2)=[O:13])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: Fc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cncnc1Oc1cc(Cl)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cncnc1Oc1cc(Cl)ccc1Cl)N1CCCc2cc(F)ccc21
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 3 %

Procedure:
To a solution of 57 mg (0.2 mmol) 4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid (Example 76, intermediate a) in 1.5 mL N,N-dimethylformamide were added 91 mg (0.24 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.102 mL (0.6 mmol) N,N-diisopropyl-ethylamine. The solution was stirred 15 minutes at 45° C. followed by addition of 36 mg (0.22 mmol) 6-fluoro-1,2,3,4-tetrahydroquinoline (commercially available, CAS RN 59611-52-8). The reaction was stirred at 45° C. overnight and purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 2.5 mg (3%) of the desired compound. MS (ESI): m/z=418.1 [M+H]+.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].O=C1CCC(=O)N1[O:41][C:42](=O)[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:42]([NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Nc1ccccn1)ON1C(=O)CCC1=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccccn4)c3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.4 g, 2.4 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) in acetonitrile (50 mL). After stirring for 30 minutes, pyridin-2-yl-carbamic acid 2,5-dioxo-pyrrolidin-1-yl ester (0.7 g, 3.0 mmol) was added, and the mixture was stirred at room temperature overnight. The solid was collected and slurried with hot acetone (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-pyridin-2-yl-urea (0.5 g, 64%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.49-2.65 (m, 2H), 2.84-2.79 (m, 1H), 4.83 (d, J=6.1 Hz, 2H), 5.14-5.21 (dd, J=5.5 and 12.7 Hz, 1H), 6.91-6.96 (m, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.64-7.88 (m, 4H), 8.17-8.20 (dd, J=1.3 and 5.0 Hz, 1H), 8.90 (t, J=5.7 Hz, 1H), 9.44 (s, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 21.96, 30.92, 38.67, 48.85, 93.31, 111.57, 116.91, 121.90, 127.20, 131.67, 133.43, 134.80, 138.23, 139.82, 146.69, 153.27, 154.93, 166.97, 167.49, 169.81, 172.75; Anal. calcd. for C20H17N5O5: C, 58.97; H, 4.21; N, 17.19. Found: C, 58.69; H, 4.10; N, 17.05.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]>CN(C)C=O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH:5]([P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:14]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1Cl)P(=O)(OCC)OCC
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a stirred solution of ethyl(diethoxyphosphoryl)acetate (10.0 g, 44.6 mmol) in N,N-dimethylformamide (100 mL) was added 60% sodium hydride in mineral oil (1.96 g, 49.1 mmol) at 0° C. and the mixture was stirred for 1 h at the same temperature. To the mixture was added 1-(bromomethyl)-2-chlorobenzene (6.35 mL, 49.1 mmol) at 0° C. and the resulting mixture was stirred for 18 h at the room temperature. The reaction mixture was quenched by the addition of water, then extracted with diethyl ether (200 mL×2), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (500 g) eluting with hexane/ethyl acetate (1/1) to afford 14.6 g (93%) of the title compound as a colorless oil:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.CS(C)=O>C(#N)C>[CH3:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:36][CH2:37][C:38]4[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])=[CH:26][CH:25]=1
Reactant: NCc1cccnc1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}ethanone (1.72 mmol), and 3-aminomethylpyridine (3.44 mmol) in dimethylsulfoxide (8.6 mmol) and acetonitrile (15 mL) was stirred at 80° C. for 18 hours. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated. The material was purified by HPLC (Normal phase, Luna CN bonded packing) and crystallized from ethyl acetate/hexane. (0.68 g; 77%), m.p. 176-177° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:15])[CH3:14])[CH2:10][C@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:14])[CH3:15])[CH2:10][C@H:9]1[CH2:16][O:17][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@@H](N(C)C)CN2C(=O)OC(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To a stirred solution of trans-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-hydroxymethyl pyrrolidine (180 mg, 0.73 mmol), methyl 4-hydroxybenzoate (114 mg, 0.75 mmol), and Ph3P (296 mg, 1.13 mmol) in THF (10 ml) was added DIAD (227 mg, 1.13 mmol) at 0° C. The reaction mixture was stirred at 70° C. for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:2, v/v) to MeOH—CH2Cl2(5:95, v/v) as eluent to give methyl 4-[trans-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-pyrrolidinyl]methoxybenzoate (180 mg, 68%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.46 (s, 9H), 1.80–1.95 (m, 1H), 2.20–2.23 (m, 1H), 2.24 (s, 6H), 2.90–2.95 (m, 1H), 3.10–3.30 (m, 1H), 3.50–3.65 (m, 1H), 3.88 (s, 3H), 3.95–4.35 (m, 3H), 6.93–6.95 (m, 2H), 7.96–7.98 (m, 2H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.[CH3:26][Si:27]1([CH2:40][CH2:41][CH3:42])[CH2:32][CH2:31][CH:30]([C@H:33]2[CH2:38][CH2:37][C@H:36](O)[CH2:35][CH2:34]2)[CH2:29][CH2:28]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:23][C@H:36]2[CH2:35][CH2:34][C@H:33]([CH:30]3[CH2:29][CH2:28][Si:27]([CH3:26])([CH2:40][CH2:41][CH3:42])[CH2:32][CH2:31]3)[CH2:38][CH2:37]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CCC[Si]1(C)CCC([C@H]2CC[C@H](O)CC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC[Si]1(C)CCC([C@H]2CC[C@H](OC(=O)c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.50 g of N,N'-dicyclohexylcarbodiimide (DCC) was added to a mixture of 1.80 g of 4-fluorobenzoic acid, 2.54 g of trans-4-(4-methyl-4-n-propyl-4-silacyclohexyl)cyclohexanol, 1.50 g of 4-dimethylaminopyridine and 30 ml of methylene chloride at room temperature. The resultant reaction mixture was agitated for 8 hours at room temperature, after which the resultant N,N'-dicyclohexyl urea was removed by filtration. The filtrate was washed with brine, dried and concentrated to obtain a residue, followed by silica gel chromatography to obtain 2.12 g (yield: 56%) of the intended product.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:21][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: BrBr
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Reaction time: 1 h
Yield: 89 %

Procedure:
6.0 g (23.7 mmol) of 9-phenylanthracene was dissolved in 80 ml of carbon tetrachloride, and a solution in which 3.80 g (21.1 mmol) of bromine was dissolved in 10 ml of carbon tetrachloride was dropped into the reaction solution by a dropping funnel. After the dropping, stirring was conducted for 1 hour at room temperature. After reaction, a sodium thiosulfate water solution was added and the reaction was stopped. An organic layer was washed with an NaOH water solution and a saturated saline and dried with magnesium sulfate. After the natural filtration, it was concentrated, dissolved in toluene, and filtered through florisil, Celite (registered trademark), and alumina. The filtrate was concentrated and recrystallized by dichloromethane and hexane. Then, 7.0 g of a light-yellow solid of 9-bromo-10-phenylanthracene, which was the intended object, was obtained with a yield of 89% (synthetic scheme of (b-4)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Agent: [Cu]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1ccccc1-c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 0.25 h

Procedure:
2-Bromonitrobenzene (Beilstein, Vol. 5, p.247; 58g) and 2,5-dibromonitrobenzene (Beilstein, vol. 5 p.250; 81g) in nitrobenzene (250 ml.) were heated at 170°-180° C. while copper powder (70 g.) was added over 15 minutes. The reaction mixture was stirred at 180° C. for 15 minutes, cooled and filtered, and the filtrate evaporated under reduced pressure. The residue was extracted into chloroform, the extract dried and evaporated, and the solid recrystallised several times from methanol to give 4-bromo-2,2'-dinitrobiphenyl, m.p. 145°-147° C. (Found: Br, 24.6 C12H7BrN2O4 requires Br, 24.8%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.Cl.[NH2:12][OH:13].CCN(CC)CC>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[NH:12][OH:13])=[C:4]([F:10])[CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N=C(NO)c1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 144.8 %

Procedure:
To a solution of 4-Bromo-2-fluorobenzonitrile 11 (800 g, 4 mol, 1 eq), hydroxylamine hydrochloride (695 g, 10 mol, 2.5 eq) in MeOH (2 L, 2.5 vol) was added Et3N (485 g, 4.8 mol, 1.2 eq), then the mixture was stirred at 60° C. for 40 min and checked by HPLC (no nitrile remaining) Reaction was then quenched by H2O (30 L), and lots of off-white solid was separated out, and then filtered, the filter cake was washed with water (10 L×2) and 1350 g wet 4-bromo-2-fluoro-N-hydroxybenzimidamide 24 was obtained with 96% purity
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11](=[O:12])[O:10][N:9]=[C:8]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.[Br:26]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:8]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:11](=[O:12])[O:10][N:9]=2)=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOCn1c(-c2ccccc2-c2ccc(C)cc2)noc1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COCCOCn1c(-c2ccccc2-c2ccc(CBr)cc2)noc1=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 53.1 %

Procedure:
A mixture of 4-[(2-methoxyethoxy)methyl]-3-(4′-methylbiphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one (46.6 g), N-bromosuccinimide (26.9 g), α,α′-azobisisobutyronitrile (2.2 g) and carbon tetrachloride (500 mL) was stirred at 80° C. for 6 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless oil (30.5 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:12]2[CH2:13][CH2:14][N:10](/[CH:9]=[CH:8]/[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=3)[C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:22][N:21]=1
Reactant: O=[N+]([O-])N=C1NCCN1C=Cc1ccc(Cl)nc1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])N=C1N(/C=C/c2ccc(Cl)nc2)CCN1Cc1ccc(Cl)nc1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
A mixture comprising 6.0 g of 1{2-(2-chloropyridin-5-yl)vinyl}-2-nitroiminoimidazolidine, 8.0 g of 2-chloro-5-chloromethylpyridine, 6.8 g of potassium carbonate and 60 ml of dimethylsulfoxide was stirred at 75° C. for 2.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate) to give 3.9 of 1-(2 chloropyridin-5-ylmethyl)-2-nitroimino-3-{trans-2-(2-chloropyridin-5-yl)vinyl}imidazolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:36](Cl)(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:34][CH:35]=1)(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCC(=O)Cl
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Product: CCCCC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccc(OC)c2)cc1
Yield: 82.9 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (238.0 mg, 0.50 mmol) and valeryl chloride (0.071 ml, 0.60 mmol), the procedure of Inventive Example 94 was repeated to obtain 232.0 mg (83.0%) of the title compound in a yellow amorphous form.