Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3SC(C)=N[C:12]=3[C:17]3[CH:22]=[CH:21][CH:20]=CC=3)([CH2:7][CH2:8]1)[O:5][CH2:4]2.CC1SC=C(C2C=CC=CC=2)N=1.BrC1C=C(C=CC=1)[O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1>>[I:1][CH2:2][C:3]12[CH2:8][CH2:7][C:6]([C:11]3[CH:20]=[CH:21][CH:22]=[C:17]([O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[CH:12]=3)([CH2:9][CH2:10]1)[O:5][CH2:4]2
Reactant: Brc1cccc(OC2CCCCO2)c1
Reactant: Cc1nc(-c2ccccc2)c(C23CCC(CI)(CC2)CO3)s1
Agent: Cc1nc(-c2ccccc2)cs1
Product: ICC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2

Procedure:
4-(Iodomethyl)-1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octane was prepared using a procedure analogous to 5-(4-(iodomethyl)-2-oxabicyclo[2.2.2]octan-1-yl)-2-methyl-4-phenylthiazole except that 2-methyl-4-phenylthiazole was replaced with 2-(3-bromophenoxy)tetrahydro-2H-pyran. The title compound was obtained (1.2 g, 2.80 mmol, 100% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.24 (t, J=8.0 Hz, 1H), 7.14-7.11 (m, 1H), 7.02 (ddd, J=7.8, 1.6, 1.0 Hz, 1H), 6.96 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 4.00-3.87 (m, 3H), 3.62 (dtd, J=11.3, 4.1, 1.2 Hz, 1H), 3.08 (s, 2H), 2.16-1.98 (m, 5H), 1.93-1.58 (m, 9H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH2:11])[CH2:5][CH2:4]1.Cl[C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1.CCN(CC)CC>COCCOC>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N:18]=2)[CH2:5][CH2:4]1
Reactant: COC1CCN(CCN)CC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC1CCN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)CC1
Yield: 78.6 %

Procedure:
Crude 2-(4-methoxy-1-piperidinyl)ethylamine (288) (3.8 g, 23.9 mmol) was added to a stirred solution of chloride 21 (1.77 g, 8.0 mmol) and Et3N (2.2 mL, 16.0 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 6 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 42 (2.16 g, 79%) as a yellow solid: mp (MeOH/EtOAc) 131-133° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.82 (br s, 1H, NH), 3.50-3.56 (m, 2H, CH2N), 3.33 (s, 3H, OCH3), 3.21-3.26 (m, 1H, CHO), 2.97-3.03 (m, 4H, H-6, H-8), 2.72-2.82 (m, 2H, CH2N), 2.60 (dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.20-2.26 (m, 2H, CH2N), 2.15 (br p, J=7.4 Hz, 2H, H-7), 1.84-1.92 (m, 2H, CH2), 1.57-1.65 (m, 2H, CH2); 13C NMR δ 158.7, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 76.2, 56.3, 55.5, 50.7 (2), 38.2, 33.1, 32.3, 30.8 (2), 25.7. Anal. calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 63.0; H, 7.4; N, 20.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:38]([O:39][CH2:40][CH2:41][CH2:42][O:43][C:44]2[C:45]([O:72][CH3:73])=[CH:46][C:47]3[C:53](=[O:54])[N:52]4[CH:55]=[C:56]([C:58]5[CH:63]=[CH:62][C:61]([N:64]6[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]6)=[CH:60][CH:59]=5)[CH2:57][C@H:51]4[CH:50]=[N:49][C:48]=3[CH:71]=2)=[CH:37][C:6]2[N:7]=[CH:8][C@@H:9]3[CH2:15][C:14](/[CH:16]=[CH:17]/[CH2:18][NH:19]C(=O)OCC4C5C=CC=CC=5C5C4=CC=CC=5)=[CH:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1>N1CCCCC1.CN(C=O)C.C(Cl)Cl>[NH2:19][CH2:18]/[CH:17]=[CH:16]/[C:14]1[CH2:15][C@H:9]2[CH:8]=[N:7][C:6]3[CH:37]=[C:38]([O:39][CH2:40][CH2:41][CH2:42][O:43][C:44]4[C:45]([O:72][CH3:73])=[CH:46][C:47]5[C:53](=[O:54])[N:52]6[CH:55]=[C:56]([C:58]7[CH:63]=[CH:62][C:61]([N:64]8[CH2:65][CH2:66][N:67]([CH3:70])[CH2:68][CH2:69]8)=[CH:60][CH:59]=7)[CH2:57][C@H:51]6[CH:50]=[N:49][C:48]=5[CH:71]=4)[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:11](=[O:12])[N:10]2[CH:13]=1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(/C=C/CNC(=O)OCC3c4ccccc4-c4ccccc43)=CN1C2=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(/C=C/CN)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.5 %

Procedure:
Piperidine (4 drops, excess) was added to a stirring mixture of Fmoc allylamine 15e (0.02 g, 0.0204 mmol, 1.0 eq.) in anhydrous DMF (0.25 mL) and the mixture was stirred at ambient temperature. After 30 minutes, the reaction mixture was diluted with DCM (30 mL) and washed with water (3×30 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was dissolved in chloroform and the resulting precipitate was collected by filtration to afford the product as an orange solid (0.001 g, 7%). LC/MS (1.495 min (ES+)), m/z: 379.5 ½[M+2H]+.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[OH-].[K+].Br[CH2:13][CH2:14][CH2:15]Br>>[O:2]1[C:1]2[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=2[O:4][CH2:15][CH2:14][CH2:13]1
Reactant: BrCCCBr
Reactant: Oc1cccc(O)c1O
Agent: [K+]
Agent: [OH-]
Product: Oc1cccc2c1OCCCO2
Temperature: 25 °C

Procedure:
63 G. of pyrogallol are dissolved with stirring in 330 ml. of absolute alcohol in a flask under a nitrogen atmosphere. 56 G. of potassium hydroxide are added to the flask and the temperature of the reaction mixture rises to 65° C. To the resulting dark-brown, clear solution, 200 g. of 1,3-dibromopropane are added dropwise a over 30 minute period. The resulting mixture is refluxed overnight with stirring. The mixture is cooled to room temperature and filtered. The ethanolic solution is evaporated to dryness and the residual oil is dissolved in 200 ml. of ether. The ether solution is washed several times with water, dried over sodium sulfate, filtered and evaporated to dryness. A dark oil, 3,4-dihydro-2H-1,5-benzodioxepin-6-ol is obtained. This oil is recrystallized from ether and petroleum ether to yield white crystals, m.p. 112°-114° C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[NH:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[CH2:10][O:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30]>C(#N)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[N:14]([S:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])(=[O:31])=[O:30])[CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[CH2:10][O:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: Brc1ccc(CC2COCc3ccccc3CN2)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COc1ccccc1S(=O)(=O)N1Cc2ccccc2COCC1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a mixture of compound 3l (900 mg, 2.7 mmol) and TEA (546 mg, 5.4 mmol) in acetonitrile (30 mL) was added 2-methoxybenzene sulfonyl chloride (559 mg, 2.7 mmol) and catalytic amount of DMAP. The reaction mixture was stirred at rt overnight. The solvent was evaporated in vacuo and purified by CC to give 3 as a white solid (510 mg, 38% yield).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Cl:1]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: ClCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCCCCCn1c(Cl)nc2ccccc21
Temperature: 60 °C
Yield: 62.2 %

Procedure:
2-chloro-1H-benzimidazole (15.2 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 5-chlorobromopentane (36.8 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 16.0 g of 1-(5-chloropentyl)-2-chloro-1H-benzimidazole, with a yield of 62.5%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1.[CH3:18][C:19]1[C:27]2[CH2:26][O:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:29][CH:30]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:18][C:19]1[C:27]2[CH2:26][O:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][N:6]1[CH2:5][CH2:4][N:3]([CH2:8][CH2:9][C:10]2[N:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:2](=[O:1])[CH2:7]1
Reactant: N#Cc1ccc(CCN2CCNCC2=O)nc1
Reactant: Cc1c(CC=O)ccc2c1COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(CCN2CCN(CCc3ccc(C#N)cn3)C(=O)C2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-[2-(2-Oxopiperazin-1-yl)ethyl]pyridine-3-carbonitrile [I-14](1 eq), (4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (1 eq) and NaBH(OAc)3 in 10 mL of DCM was stirred overnight at RT. The mixture was diluted with 50 mL of DCM and washed with brine, concentrated and the residue was purified by prep-TLC (DCM:MeOH=15:1) to afford the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 8.73 (s, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 5.18 (s, 2H), 3.71 (t, J=7.2 Hz, 2H), 3.26 (s, 2H), 3.08-3.14 (m, 4H), 2.85 (t, J=7.6 Hz, 2H), 2.65 (s, 2H), 2.54 (t, J=7.6 Hz, 2H), 2.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]([C:9]#[N:10])[C:7]=1F.NC1C=C(C(F)(F)F)C=C(Cl)C=1F.[Cu]C#N.[CH3:31][C:32]1[C:37](=[O:38])[NH:36][CH:35]=[N:34][C:33]=1[C:39]([F:42])([F:41])[F:40]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]([C:9]#[N:10])[C:7]=1[N:36]1[C:37](=[O:38])[C:32]([CH3:31])=[C:33]([C:39]([F:40])([F:41])[F:42])[N:34]=[CH:35]1
Reactant: Cc1c(C(F)(F)F)nc[nH]c1=O
Reactant: N#Cc1cc(C(F)(F)F)cc(Cl)c1F
Agent: N#C[Cu]
Agent: Nc1cc(C(F)(F)F)cc(Cl)c1F
Solvent: CC#N
Solvent: O
Product: Cc1c(C(F)(F)F)ncn(-c2c(Cl)cc(C(F)(F)F)cc2C#N)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylpyrimidin-6-one was prepared by the reaction of the product of Preparation 2 of EP 0 398 499 (i.e., 3-chloro-4-fluoro-5-cyano-trifluoromethylbenzene, produced as follows: A solution of 3-amino-5-chloro-4-fluorotrifluoromethylbenzene (3 g) in acetonitrile (10 ml) was added dropwise to a stirred suspension of copper (I) cyanide (1.26 g) in dry acetonitrile (50 ml) whilst the reaction temperature was maintained at 0° C. After the addition was complete, the reaction mixture was allowed to warm to the ambient temperature (about 23° C.) and left overnight. The reaction mixture was poured into water, extracted with diethyl ether, dried over anhydrous magnesium sulphate and filtered. Evaporation of the solvent, under reduced pressure, gave a brown oil, which was flushed through a plug of silica gel using petroleum ether (boiling range 60°-80° C.) containing diethyl ether (20% by volume) as eluent. After removal of the solvent, under reduced pressure, Kugelrohr distillation of the residue gave two fractions, the first of which (boiling point 110° C. at 15 mmHg) was predominantly composed of 3-chloro-4-fluoro-5-cyano-trifluoromethylbenzene and 5-methyl-4-trifluoromethylpyrimidin-6-one. The product had a melting point of 154.1°-154.9° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Cl[CH2:55][C:56]([NH2:58])=[O:57]>O>[C:56]([CH2:55][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)(=[O:57])[NH2:58]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OCC(N)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 56.8 %

Procedure:
In a 15 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol) and cesium carbonate (63.4 mg, 195 μmol) were combined with dimethyl formamide (2 mL). 2-Chloroacetamide (15.2 mg, 162 μmol) was added to the mixture with stirring to give a white suspension. The tube was capped and heated at 50° C. overnight. The reaction mixture was cooled down to room temperature. It was poured into water and extracted with ethyl acetate (2×). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with ethyl acetate in hexanes) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid carbamoylmethyl ester as an off-white solid (62 mg, 58% yield). LCMS (ES+) m/z calcd. for C33H33Cl2F2N4O5 [(M+H)+]: 673. found: 673.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([Mg]Br)[CH3:16].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([CH:13]([OH:14])[CH2:15][CH3:16])=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cnc(-c2cccc(F)c2)s1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1cnc(-c2cccc(F)c2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of 2-(3-fluorophenyl)thiazole-5-carbaldehyde (0.320 g, 1.545 mmol) in THF (12 mL) was added 3.0 M solution of ethyl magnesium bromide in diethyl ether (1.28 mL, 3.86 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stir for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and water (5 mL), extracted with ethyl acetate (50 mL), dried over sodium sulphate and concentrated under reduced pressure to obtain crude product. The crude compound was purified by Biotage Isolera® One chromatograph (using 15% ethyl acetate and hexane) to afford 1-(2-(3-fluorophenyl)thiazol-5-yl)propan-1-ol (0.18 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.68 (d, 3H), 7.40 (q, 1H), 7.11 (t, 1H); 4.93 (t, 1H), 4.11 (q, 1H), 1.90-1.87 (m, 2H), 1.01 (t, 3H); LC-MS m/z calcd for [M+H]+ 238.06. found 238.0.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)[CH2:25][CH2:24][C:23](=O)[NH:22][CH2:21]2)[CH:16]=[CH:17][C:18]=1[Cl:19].O1CCCC1.O>O1CCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([CH2:27][CH2:28][OH:29])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CC(C)(C)[Si](C)(C)OCCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCC1(c2ccc(Cl)c(Cl)c2)CCCNC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Combine a solution of lithium aluminum hydride (42 mL, 1 M in THF, 42.0 mmol). Cool to about −10° C. using an isopropyl alcohol/ice bath. Slowly add a solution of sulfuric acid (1.15 mL, 21.6 mmol) in tetrahydrofuran (4 mL) at such a rate that the reaction temperature does not rise above −10° C. Stir vigorously and warm to ambient temperature. After 2 hours, add a solution of 3-(3,4-dichlorophenyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-6-oxopiperidine (5.56 g, 13.85 mmol) in tetrahydrofuran (12 mL). Heat to reflux. After 18 hours, add 1/1 tetrahydrofuran/water. After 1 hour, filter and rinse with dichloromethane. Suspend the solids removed by filtration in tetrahydrofuran (400 mL). To the tetrahydrofuran suspension add water (20 mL) and 15% aqueous sodium hydroxide solution (8 mL) and stir vigorously. After 2 hours, filter. Combine the filtrates and concentrate in vacuo to give an aqueous suspension. Extract twice with dichloromethane. Dry the organic layers over Na2SO4, filter, and concentrate in vacuo to give the title compound.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[N:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][C:11]=1[Cl:21])(=O)C.Cl>CO.C(Cl)Cl.CO>[C:17]([C:13]1[CH:12]=[C:11]([Cl:21])[C:10]([N:9]=[C:5]2[NH:6][CH2:7][CH2:8][NH:4]2)=[C:15]([Cl:16])[CH:14]=1)([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(Cl)c(N=C2NCCN2C(C)=O)c(Cl)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Yield: 81 %

Procedure:
A solution of 1-acetyl-2-(4-carbomethoxy-2,6-dichlorophenylimino)imidazolidine (5 g, 15 mmole) and 2M hydrochloric acid (1 ml, 2 mmole) in methanol (100 ml) was heated under reflux for 40 hour. The mixture was then evaporated to give a solid which was taken up in methylene chloride/methanol (650 ml:30 ml) and extracted with saturated sodium carbonate (300 ml). The organic layer was dried and evaporated to give a residue which after trituration with ether, yielded the title compound as a solid (3.5 g) mp 229°-231° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH:27]([CH3:29])[CH3:28]>>[CH3:26][CH:27]([CH3:29])[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC(C)CBr
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Product: CC(=O)NC(C)c1cc2ccc(CCc3ccc(OCC(C)C)cc3)cc2o1
Yield: 27 %

Procedure:
Using N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (32.3 mg, 0.100 mmol) obtained in Example 165 and 1-bromo-2-methylpropane (0.0225 mL, 0.200 mmol) and in the same manner as in Example 158, the title compound was obtained (10.3 mg, yield 27%) as a white solid.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25]([O:27][C:28](=[O:44])[CH2:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)[CH3:26]>COCCOC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:25]([O:27][C:28](=[O:44])[CH2:29][N:30]1[CH:34]=[C:33]([C:2]2[S:6][CH:5]=[C:4]([C:7]([N:9]3[CH:18]4[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:12][CH2:11][CH2:10]3)=[O:8])[CH:3]=2)[CH:32]=[N:31]1)[CH3:26]
Reactant: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cn1cc(-c2cc(C(=O)N3CCCC4CCCCC43)cs2)cn1
Temperature: 140 °C
Yield: 61.9 %

Procedure:
cis-(5-Bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)-methanone (0.217 g, 0.66 mmol) was added to a solution of caesium carbonate (0.32 g, 0.99 mmol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]acetic acid ethyl ester (0.203 g, 0.725 mmol) and palladium tetrakis(triphenylphosphine) (76 mg, 0.07 mmol) in DME (6 mL), IMS (2 mL) and water (1 mL). The reaction mixture was purged with nitrogen and heated by microwave irradiation to 140° C. for 20 minutes then diluted with water and extracted with DCM (×2). The organic solution was dried over sodium sulfate, filtered and the solvent evaporated. The crude material was purified by chromatography on a 5 g silica II cartridge, eluting with 10-50% ethyl acetate in cyclohexane then columned using 0-25% diethyl ether in DCM to afford {4-[4-(octahydro-quinoline-1-carbonyl)-thiophen-2-yl]-pyrazol-1-yl}-acetic acid ethyl ester (164 mg). LCMS m/z 402.41 [M+H]+ R.T.=3.91 min (Analytical Method 6).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([Br:13])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C1OC1C>C(COC)OC>[Br:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([Cl:12])=[CH:11][C:2]3[N:3]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:1]=3)=[CH:8][CH:7]=1
Reactant: Nc1cc(Cl)c2ccc(Br)cc2n1
Reactant: CCOC(=O)C(=O)CBr
Agent: CC1CO1
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(cc(Cl)c3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 g of 2-amino-7-bromo-4-chloroquinoline was suspended in 10 ml of dimethoxyethane and then a solution of 1 g of ethyl bromopyruvate and 300 mg of propylene oxide in 10 ml of dimethoxyethane was added. The mixture was stirred at room temperature for 2 days and 300 mg of ethyl bromopyruvate were then added. Stirring was continued for a further day and the precipitated quaternary salt was filtered off, washed with ether and then was suspended in 20 ml of ethanol. The mixture was heated at reflux for 2 hours and the solvent was removed under vacuum. The residue was partitioned between CHCl3 /Na2CO3 solution and the organic solution was dried over MgSO4 and the solvent was removed to leave a cream solid. This was purified by chromatography over silica with 5% methanol in chloroform as eluent and the product was crystallized from chloroform/ether to obtain pale cream needles of ethyl 8-bromo-5-chloroimidazo-[1,2-a]-quinoline-2-carboxylate melting at 206° to 207° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:21][CH:22]([CH3:50])[CH2:23][CH:24]([CH2:27][O:28][C:29](=[O:49])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:25][OH:26])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH3:1][S:2]([O:26][CH2:25][CH:24]([CH2:23][CH:22]([O:21][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:50])[CH2:27][O:28][C:29](=[O:49])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)CC(C)OC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COS(C)(=O)=O)CC(C)OC(=O)c1ccccc1

Procedure:
Using 0.358 ml (4.63 mM) of methanesulfonyl chloride and 0.814 ml (5.79 mM) of triethylamine, 2.059 g (3.86 mM) of 2-(2-benzoyloxypropan-1-yl)-3-octadecylcarbamoyloxypropanol m7 in dichloromethane is converted to the crude titled compound m7a by the same procedure as described in (50).