Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[C:25][CH2:26][OH:27])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:28].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([O:27][CH2:26][C:25]#[C:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:29]=[CH:30][CH:31]=[C:2]([F:1])[CH:3]=2)=[C:8]([Cl:28])[CH:9]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: OCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of 3-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)prop-2-yn-1-ol (compound 10.1, 800 mg), triethyl amine (0.4 mL) in dichloromethane (20 mL) at 0° C. was added MsCl (0.16 mL) and the reaction mixture was warmed to room temperature. The reaction was washed with saturated NaHCO3 aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with EtOAc to give the desired product. LCMS ESI(+) m/z: 513 (M+1). Yield: 43%.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:20][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCCN2CCCC2)c(F)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
1-(2-Chloro-ethyl)-pyrrolidine hydrochloride (1.2 g, 7.0 mmol, 1.1 equiv) is added to a suspension of 2-fluoro-4-nitrophenol (1 g, 6.4 mmol) and cesium carbonate (5.2 g, 15.9 mmol, 2.5 equiv) in DMF (20 mL). The resulting mixture is heated to 80° C. and stirred for 18 h. Additional 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1 g) is added and the mixture is stirred for 3 h at 80° C. The reaction mixture is cooled to RT, diluted with EtOAc and H2O. The layers are separated and the aqueous layer is extracted with EtOAc. The organic phase is washed with H2O, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) to provide the title compound as a yellow solid. ESI-MS: 255.1 [MH]+; tR=2.57 min (system 1); TLC: Rf=0.55 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Cl>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:19][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: NCC1CCNCC1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
After dissolving 4-aminomethylpiperidine (13.7 g, 120 mmol) in acetonitrile (200 ml), potassium carbonate (11.057 g, 80 mmol) and 3,4-dichlorobenzyl chloride (7.818 g, 40 mmol) were added and the mixture was stirred at 60° C. overnight. After completion of the reaction, the reaction mixture was filtered and the solvent was distilled off. Purification was performed by silica gel column chromatography (dichloromethane/methanol/triethylamine=90/5/5) to obtain {1-[(3,4-dichlorophenyl)methyl]-4-piperidyl}methylamine. The compound was identified by LC-MS.
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:42][O:43][CH2:44][CH2:45]Br>CN(C=O)C.O>[CH3:42][O:43][CH2:44][CH2:45][O:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(Cn2ncc3cc(C=C4SC(N5CCN(C)CC5)=NC4=O)ccc32)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
5-[1-(4-Hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one (24.7 mg, 0.049 mmol) was dissolved in 1 mL of dry DMF. To the DMF solution was added Cs2CO3 (31.9 mg, 0.098 mmol), followed by methoxyethyl bromide (9.6 mg, 0.07 mmol). The mixture was stirred at 60° C. for 16 h and then diluted with water. It was extracted with EtOAc and the combined EtOAc extracts were washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (0-100% gradient CH2Cl2/EtOAc, followed by 10% MeOH/EtOAc) to afford the title compound (21 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[CH:12]=[CH:13][C:14]([N+:26]([O-:28])=[O:27])=[C:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=1.[H-].[Na+]>CN(C)C=O>[CH3:25][N:17]([C:15]1[CH:16]=[C:11]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:12]=[CH:13][C:14]=1[N+:26]([O-:28])=[O:27])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 85.7 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-methoxyphenol (5.0 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (10.9 g), sodium hydride (55 wt. %, 2.2 g) and anhydrous N,N-dimethylformamide (120 ml) and the reaction mixture was purified to give the title compound (12.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:30][CH2:31][CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH:30][CH2:31][CH2:32][C:33]2[N:37]=[CH:36][NH:35][CH:34]=2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCc1c[nH]cn1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCc2c[nH]cn2)ccc1Cl

Procedure:
Synthesized from 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 6e, 1 mg) and histamine according to the procedure described in Example 6f to afford the title compound.
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[Na].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN(C)C=O.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([Si:3]([CH3:5])([CH3:4])[CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(CCl)c1ccc(Cl)cc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(Cn1ccnc1)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of 2.2 g (0.010 mol) of chloromethyl(4-chlorophenyl)dimethylsilane and 1.1 g (0.012 mol) of imidazole sodium salt in 5 ml of dimethylformamide was stirred at 80°-90° for 2 hours, cooled, diluted with water, and extracted with ether. The ether solution was washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2.0 g (81%) of the title compound as a yellow liquid: nD20 1.5472; ir (neat) 1560, 1495, 1480, 1375, 1250, 1105, 1080, 905, 830, 810, 740 cm-1 ; nmr (CDCl3) 0.3 (6H, s), 3.6 (2H, s), 6.6 (1H, broad s), 6.9 (1H, broad s), 7.1 (1H, broad s), 7.3 (4H, s).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([CH:44]([CH3:46])[CH3:45])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([CH2:10][CH2:11][O:12][Si](C(C)(C)C)(C)C)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([CH:44]([CH3:46])[CH3:45])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO[Si](C)(C)C(C)(C)C)c4ccccc43)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a solution of Intermediate 10d (100 mg, 0.15 mmol) in THF (2 mL), TBAF (1M in THF, 0.23 mL, 0.23 mmol) was added at RT and stirred for 10 min. The reaction mixture was diluted with H2O (5 mL) and DCM (5 mL). The layers were separated, and aqueous layer was extracted with DCM (3×5 mL). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and then purified by FCC using 0-5% [2M NH3 in MeOH] in DCM). The residue was washed with water and purified by HPLC (30%-100% MeCN in H2O, 0.1% formic acid) to give the title compound as a white powder (47 mg, 57%). Rf=0.2 (5% [2M NH3 in MeOH] in DCM) LCMS (Method 5): Rt 3.59 min, m/z 532 [MH+]. 1H NMR (400 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): 1.25 (s, 9H), 1.43 (d, J=6.9 Hz, 3H), 1.46 (d, J=6.9 Hz, 3H), 1.92-2.30 (m, 4H), 3.25 (p, J=6.9 Hz, 1H), 3.95 (t, J=4.7 Hz, 2H), 4.15 (dd, J=5.3, 3.5 Hz, 2H), 5.09-5.16 (m, 1H), 5.92 (d, J=8.0 Hz, 1H), 6.12 (s, 1H), 6.92 (dd, J=9.8, 1.9 Hz, 1H), 7.22-7.27 (m, 2H), 7.33 (td, J=5.8, 3.0 Hz, 1H), 7.40 (s, 1H), 7.43 (br s, 2H), 7.47 (d, J=7.8 Hz, 1H), 7.70 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].[I-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH2:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.8 %

Procedure:
1.81 g of Compound 27 was dissolved in 60 ml of dimethylformamide, 208 mg of sodium hydride (60% oil dispersion), 1.67 g of N-(3-bromopropyl)phthalimide and 156 mg of sodium iodide were added and the mixture was stirred at room temperature for 2.5 hours. Additional 104 mg of sodium hydride (60% oil dispersion) and 697 mg of N-(3-bromopropyl)phthalimide were added and the mixture was stirred at room temperature for 1.8 hours. Additional 62.4 mg of sodium hydride (60% oil dispersion) and 418 mg of N-(3-bromopropyl)phthalimide were added and the mixture was stirred at room temperature for 2 hours. An aqueous solution of ammonium chloride was added to the reaction solution, the solvent was distilled off under reduced pressure and the residue was extracted once with chloroform. The chloroform layer was washed with an aqueous saturated solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:methanol=100:1-60:1) and recrystallized from chloroform/n-hexane to give 1.72 g (62%) of Compound 28.
Reaction SMILES: [CH:1]1([CH:4]([OH:8])[CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>O1CCCC1>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[CH2:12][O:8][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][CH:6]=[CH2:7])[CH3:16]
Reactant: CCOC(CBr)OCC
Reactant: C=CCC(O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(OCC(OCC)OCC)C1CC1
Temperature: 25 °C

Procedure:
1-Cyclopropylbut-3-en-1-ol (C48, see C. Tahtaoui et al., J. Org. Chem. 2010, 75, 3781-3785) (92%, 8.1 g, 66 mmol) was added to a 0° C. suspension of sodium hydride (60% in mineral oil, 8.25 g, 206 mmol) in tetrahydrofuran (105 mL). The cooling bath was removed and the suspension was stirred until the internal temperature reached 21° C. The reaction mixture was then cooled in an ice bath, and 2-bromo-1,1-diethoxyethane (97%, 18.5 mL, 119 mmol) was added drop-wise at a rate that maintained the internal temperature below 5° C. After warming to room temperature, the reaction mixture was heated to 58° C. for 27 hours. Sodium hydride (60% in mineral oil, 3.3 g, 83 mmol) and 2-bromo-1,1-diethoxyethane (97%, 10 mL, 64 mmol) were added again, and the reaction mixture was heated at mild reflux for 14 hours. It was then cooled to 0° C., slowly quenched with water (100 mL) and extracted with diethyl ether (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 12.1 g, 53.0 mmol, 80%. 1H NMR (400 MHz, CDCl3) δ 5.87-5.98 (m, 1H), 5.05-5.11 (m, 1H), 5.00-5.04 (m, 1H), 4.61 (t, J=5.3 Hz, 1H), 3.66-3.75 (m, 3H), 3.54-3.62 (m, 2H), 3.47 (dd, J=10.3, 5.5 Hz, 1H), 2.70 (dt, J=8.4, 6.0 Hz, 1H), 2.36-2.41 (m, 2H), 1.22 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H), 0.80-0.90 (m, 1H), 0.54-0.62 (m, 1H), 0.35-0.50 (m, 2H), 0.07-0.14 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][CH:6]=1.[SH2:8]>>[Cl:1][C:2]1[S:3][C:4]([S:8][C:4]2[S:3][C:2]([Cl:1])=[CH:6][CH:5]=2)=[CH:5][CH:6]=1.[Cl:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][CH:6]=1
Reactant: S
Agent: Clc1ccc(Br)s1
Product: Clc1ccc(Sc2ccc(Cl)s2)s1

Procedure:
By a procedure similar to that described in Example 3, at a temperature of 480° C, from 2-chloro-5-bromothiophene and hydrogen sulphide taken in the molar ratio of 2:1 respectively, di(2-chloro-5-thienyl)sulphide is obtained in the quantity of 17 percent by weight with respect to the starting quantity and 30 percent by weight for the reacted 2-chloro-5-bromothiophene.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O.[BH4-].[Na+].O>C(O)(=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]([NH:1][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[O:19][CH3:18])=[C:3]([CH:13]=1)[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccc(Cl)cc1C(O)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CNc2ccc(Cl)cc2C(O)c2ccccc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 2-amino-5-chloro-α-(2-chloro phenyl)benzyl alcohol (5.0 g) and 2,4-dimethoxy benzaldehyde (3.72 g) in acetic acid (50 ml) was added, under ice-cooling, sodium borohydride (0.94 g). The mixture was stirred for one hour at room temperature, which was poured into water (200 ml), followed by extraction with ethyl acetate (200 ml×2). The ethyl acetate layer was washed with 1N sodium hydroxide, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=5:1) to give 5-chloro-α-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)aminobenzyl alcohol (7.5 g) as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCCCCCCCBr
Reactant: Oc1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCCOc1ccc(F)cc1
Yield: 106.4 %

Procedure:
12-Bromododecanoic acid (1 g) was stirred in 10% hydrochloric acid-methanol for 4 hours. The mixture was then concentrated and distributed into chloroform and water, and the chloroform layer was dried with anhydrous sodium sulfate to give the methyl ester of 12-bromoundecanoic acid (1.01 g). To para-fluorophenol (0.38 g) dissolved in dimethylformamide (DMF) was added 60NaH (0.40 g), and the mixture was stirred. To this mixture was added 12-bromododecanoic acid (1 g), and the mixture was stirred for 12 hours. The reaction mixture, after having been concentrated and adjusted to a weak acidic range of pH by adding citric acid, was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to give 12-para-fluorophenoxydodecanoic acid (1.12 g). The product was dissolved in a mixed solvent of ethanol-water (1:1), and potassium hydroxide (0.6 g) was added to the solution. The mixture was stirred at 80° C. for 30 minutes. The reaction mixture was diluted with water (80 ml), adjusted to acidic range of pH by adding citric acid, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 12-para-fluorophenoxy-dodecanoic acid (1.03 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=O)[NH2:17])=[O:10])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCCC1C(N)=O
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCCC1C#N
Temperature: -35 °C
Yield: 84.8 %

Procedure:
In a dry three-neck flask under a nitrogen atmosphere, 286 mL of pyridine, [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (13.5 g, 49.8 mmol) and imidazole (7.11 g, 104.6 mmol) were added successively. The reaction system was cooled down to −35° C., and phosphorus oxychloride (19 mL, 204.2 mmol) was then added dropwise to the solution with stirring. After stirring for 1 hour at −35° C., the reaction mixture was allowed to increase to room temperature, and stirred for another 0.5 hour. Pyridine was evaporated under low temperature, and the reaction mixture was diluted with water, then extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound [2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1e (10.7 g, yield 84.9%) as a white powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]>O1CCCC1.CO.[C].[Pd]>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C=Cc2cccc(CC(=O)O)c2)cs1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1nc(CCc2cccc(CC(=O)O)c2)cs1
Yield: 91.7 %

Procedure:
3-{2-[2-(Acetylamino)-1,3-thiazol-4-yl]vinyl}phenylacetic acid (4.500 g, 14.88 mmol) was dissolved in a mixed solvent of tetrahydrofuran (225 ml) and methanol (90 ml), and 20% palladium carbon (containing 50% water, 1.800 g) was added. Hydrogenation was performed at room temperature −30° C., 4 atm. After the completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated. Diethyl ether (100 ml) was added to the residue, and the precipitate was collected by filtration. The filtered product was washed 3 times with diethyl ether, and dried under reduced pressure to give 3-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenylacetic acid (4.152 g, 13.64 mmol, yield 91.7%) as a white solid.
Reaction SMILES: [Cl:1][C:2]([O:5]C=O)(Cl)Cl.[CH2:8]([NH:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:9]=[CH2:10].C(N(CC)CC)C>ClCCl>[CH2:8]([N:11]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]([Cl:1])=[O:5])[CH:9]=[CH2:10]
Reactant: O=COC(Cl)(Cl)Cl
Reactant: C=CCNC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(C(=O)Cl)C1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
790 mg (0.48 ml, 3.99 mmol) of trichloromethylformate (“diphosgene”) are dissolved in 15 ml of dichloromethane and cooled to 0° C. To this are slowly added dropwise 1.00 g (1.17 ml, 7.986 mmol) of allyl(cyclopentyl)amine and 1.21 g (1.67 ml, 12.0 mmol) of triethylamine, and the mixture is left to stir at room temperature overnight. For workup, the reaction solution is poured into ice-water, extracted three times with dichloromethane, dried over MgSO4 and concentrated. The crude product is employed directly in the next stage.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:12]([CH3:11])(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 63.9 %

Procedure:
4-Nitro-phenylamine (25 g, 181 mmol) was dissolved in pyridine (450 mL). Methanesulfonyl chloride (14.0 mL, 181 mmol) was added dropwise while stirring. The mixture was stirred for 16 h at 25° C. The solution was concentrated in vacuo to a volume of ˜50 mL. The mixture was diluted with ethyl acetate (400 mL), washed with 1.0 M aqueous hydrochloric acid solution (5×200 mL). The combined aqueous layers were back-extracted with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to a volume of ˜250 mL. The product precipitated and was collected by vacuum filtration. The filtrate was concentrated in vacuo to a volume of ˜125 mL upon which additional product precipitated. The solid was collected by vacuum filtration. The solids were combined to afford the desired product, N-(4-nitro-phenyl)-methanesulfonamide (25 g, 115.62 mmol, 64% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.17 (3H, s), 7.35 (2H, d, J=9.4 Hz), 8.20 (2H, d, J=9.1 Hz), 10.69 (1H, s).