Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][O:39][C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][N:41]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:38][O:39][C:40]1[N:45]=[CH:44][C:43]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7]4[N:15]=[CH:16][CH:17]=[CH:18][C:6]=4[N:5]3[C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[CH2:27][CH2:28][CH2:29]3)=[CH:24][CH:25]=2)=[CH:42][N:41]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: COc1ncc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cn1
Yield: 85.1 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.090 mmol), (2-methoxy pyrimidin-5-yl)boronic acid (28 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.09 mmol), and 2M Na2CO3 aq. (0.090 mL, 0.18 mmol) in DMF (2.5 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:2) to afford the desired product (45 mg, 86%) as a yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.70 (s, 2H), 8.12 (dd, J=7.4 Hz and 1.7 Hz, 1H), 8.02 (d, J=3.4 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.33 (td, J=8.0 Hz and 1.7 Hz, 1H), 7.18-7.14 (m, 2H), 6.97-6.94 (m, 1H), 6.82-6.79 (m, 1H), 6.61 (dd, J=8.0 Hz and 5.2 Hz, 1H), 6.25 (s, 1H), 5.07 (br s, 1H), 4.01 (s, 3H), 2.57-2.38 (m, 4H), 2.19-2.12 (m, 1H), 1.94-1.86 (m, 1H), 1.39 (br s, 9H). LCMS: 588 [M+H].
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:24][N:10]([CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([CH2:2][O:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:4][CH2:5]1)[S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: CN(C[C@H]1CC[C@H](CO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Product: CN(C[C@H]1CC[C@H](COS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-N-(4-hydroxymethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide is treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexylmethyl ester as colorless solid, MS: 443 (M+).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C:7]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)C.[Li+].[OH-].[OH-].[Na+].C(O)=O>C1COCC1.CCO>[C:27]([O:26][CH:5]([C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C:7]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:4]([OH:31])=[O:3])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(OC)cccc2c1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CCO
Product: COc1cccc2c(-c3ccc(Cl)cc3)c(C(OC(C)(C)C)C(=O)O)c(C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of tert-butoxy-[1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-acetic acid ethyl ester (12 mg) in THF (0.3 mL) and EtOH (0.1 mL) was added 0.1 mL of 1 M LiOH. The reaction was stirred for 30 min at room temperature, then 0.3 mL each of THF, EtOH, and 1 M NaOH were added. The reaction was heated to 70° C. for 2.5 hours, and then cooled to room temperature. Formic acid was added until pH ˜5. The reaction mixture was directly purified by HPLC (Gemini, 50-100% MeCN/H2O, with 0.1% TFA). The product was lyophilized to give a white powder (8 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[C:6]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1C(C)(C)C

Procedure:
A mixture of 30.0 g 3-(1,1-dimethylethyl)-4-hydroxybenzoic acid methyl ester, 42.9 ml of 1-bromotetradecane, 47.8 g of potassium carbonate and 700 ml of acetone is refluxed for 48 hours. The cooled reaction is filtered, concentrated in vacuo and purified by column chromatography (silica ge1:0-3% ethyl acetate/hexane) to give 38.8 g of the desired product as colorless prisms.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=O)[CH2:4][CH2:3][CH2:2]1.Cl.[O:9]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C1COCC1>[O:9]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[O:7])=[CH:22][CH:23]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C1CCC1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Oc2ccccc2)cc1)C1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a cooled (0° C.) solution of cyclobutanecarboxylic acid (0.26 g, 2.6 mmol), 4-phenoxybenzylamine hydrochloride (0.62 g, 2.6 mmol), HOBt, (0.71 g, 5.2 mmol) and triethylamine (1.1 mL, 7.83 mmol) in THF (9 mL) was added EDCl (0.55 g, 2.6 mmol). The mixture was stirred for 18 hours at room temperature. The solvent was removed, and the residue was suspended in ether and washed with 0.1N HCl, 5% NaHCO3 and brine. The ether layer was dried (MgSO4), filtered through a plug of silica gel and concentrated in vacuo to provide 0.70 g (96%) of the title compound as a white solid. m.p. 69°-71° C. 1H NMR (CDCl3, 300 MHz) δ1.80-2.06 (m, 2H), 2.10-2.14 (m, 2H), 2.15-2.39 (m, 2H), 3.02 (pd, J=7.5, 1.2 Hz, 1H), 4.41 (d, J=6 Hz, 2H), 5.55 (br s, 1H), 6.94-7.04 (m, 4H), 7.08-7.15 (tt, J=7.5, 1.5 Hz, 1H), 7.20-7.28 (m, 2H), 7.30-7.38 (m, 2H). MS (DCl/NH3) m/e 282 (M+H)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:17][C:18]#[N:19]>CN(C)C=O>[N:1]1([CH2:17][C:18]#[N:19])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: N#CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To an ice cooled solution of benzimidazole (10 g, 0.085 mol) in dry N,N-dimethylformamide (500 mL) was added potassium tert-butoxide (9.6 g, 0.085 mol) portionwise. The mixture was stirred at room temperature for 1 h then bromoacetonitrile (6 mL, 0.086 mol) was added in one portion and stirred for 3 h. The mixture was then quenched with solid carbon dioxide followed by water and the organics separated. The organics were washed further with water (100 mL×5), and brine (100 mL×1) combined and dried (Na2SO4), filtered and evaporated to dryness. The residue was passed through a silica gel column eluting with dichloromethane:ethanol (1% up to 6% ethanol) to give a yellow solid (12 g, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 5.08 (2H, s), 7.36-7.43 (2H, m), 7.47 (1H, d, J=7.4 Hz), 7.85 (1H, d, J=7.2 Hz), 7.93 (1H, s).
Reaction SMILES: [CH:1]1([CH2:4][C:5]#[N:6])[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.[NH4+].[Cl-].OS(O)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH:29]1(N)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CCOCC.C(OCC)(=O)C>[CH:1]1([CH2:4][CH:5]=[N:6][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: N#CCC1CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C(CC1CC1)=NC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of cyclopropylacetonitrile (7.0 ml, 82 mmol) in 200 ml of methylene chloride/hexanes (1:1) at -78° C. was added 90.0 ml of 1M DIBAL in hexanes (90 mmol) dropwise over 20 minutes. After complete addition, the solution was warmed to 0° C. and stirred for 2 hours. At this time, 140 ml of ethyl acetate was added at 0° C. and the solution warmed to room temperature. To the solution was added 140 ml of saturated NH4Cl and 250 ml of 1N H2SO4. The mixture was diluted with ether and shaken vigorously until the organic layer became clear. The organic layer was then washed with saturated NaHCO3. To this crude aldehyde solution was added 55 g of K2CO3 and 9.4 ml of cyclohexylamine (82 mmol) at room temperature and the reaction stirred for 48 hours. The reaction was filtered and evaporated and the residue distilled under reduced pressure to give the title compound. MS 166 (M+H)+ ; 1H NMR (CDCl3) δ0.12-0.19 (m, 2H), 0.46-0.53 (m, 2H), 0.76-0.91 (m, 1H), 0.95-1.90 (m, 10H) , 2.12 (dd, 2H, J=5.2 Hz, J=7.4 Hz), 2.93 (m, 1H), 7.71 (t, 1H, J=5.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)[CH:16]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2cccc(C(F)(F)F)c2)c1
Yield: 60.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-(trifluoromethyl)benzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 3-(trifluoromethyl)phenylboronic acid (0.033 g; 0.173 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.346 mmol), sodium iodide (0.052 g; 0.346 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.048 g (61%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].[NH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([C:44](=[O:46])[CH3:45])[CH2:40][CH2:39]1>>[C:44]([N:41]1[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][NH:35][C:31](=[O:33])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:39][CH2:40]1)(=[O:46])[CH3:45]
Reactant: CC(=O)N1CCN(CCN)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Product: CC(=O)N1CCN(CCNC(=O)Cc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1

Procedure:
{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid was coupled with 1-[4-(2-amino-ethyl)-piperazin-1-yl]-ethanone to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:57][CH2:58][CH2:59][N:60]1[CH2:65][CH2:64][NH:63][C:62](=[O:66])[CH2:61]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][NH:63][C:62](=[O:66])[CH2:61]2)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: NCCN1CCNC(=O)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (100 mg, 0.19 mmol), HOBt (3 mg, 0.1 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 4-(2-amino-ethyl)-piperazin-2-one (30 mg, 1.1 eq.) in DMF (2 mL) at rt was added TEA (0.067 mL, 2.5 eq.). After stirring at rt for 7 days, the reaction was concentrated, diluted with DCM and then mixed with solid sodium bicarbonate. After stirring at rt for 15 mins, the suspension was loaded onto a silica gel column to give the titled compound as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[Cl-].[Ca+2].[Cl-].C(O)C>O>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([OH:12])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1cc(O)c(Cl)cc1F
Yield: 79.6 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrophenol (28.6 g, 0.150 mol), reduced iron (41.6 g, 0.745 mol), calcium chloride (8.28 g, 74.6 mmol) and ethanol (540 mL)/water (60 mL) was stirred with heating under reflux for 3.5 hr. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and ethyl acetate (700 mL) was added to the residue. The solution was washed with water (200 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→50/50) to give the title compound (19.3 g, 80%) as a brown powder.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].Cl[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>ClC(Cl)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:8][Si:9]([C:12]#[C:13][C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:11])[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: Clc1nc2ccccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1nc2ccccc2o1
Temperature: 80 °C

Procedure:
A mixture of bis(triphenylphosphine)palladium(II) chloride (0.229 g, 0.326 mmol), triethylamine (1.815 mL, 13.02 mmol), copper(I) iodide (0.124 g, 0.651 mmol), trimethylsilylacetylene (29A, 1.645 mL, 11.72 mmol) and compound 28A (1.0 g, 6.51 mmol) in dichloroethane (10 mL) under an inert atmosphere was heated at 80° C. overnight. After the reaction was complete, the mixture was cooled, diluted with dichloromethane (10 mL), washed with aq. NaHCO3, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0-5% EtOAc/hexanes to give a mixture of Compound 29B (575 mg) and Compound 29C (200 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[NH:17]2)=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+].I[CH2:45][CH3:46]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH2:45][CH3:46])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2)cc1)Oc1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2CC)cc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A slurry of 2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester (0.500 g, 0.875 mmol) and sodium hydride (0.039 g, 0.96 mmol, 60% dispersion on mineral oil) in DMF (10 mL) is stirred for 1 hour, then cooled to 0° C. Iodoethane (0.70 mL, 8.75 mmol, d=1.975) is added, then the reaction mixture is stirred 18 hours at ambient temperature and diluted with ethyl acetate. The organic layer is washed, dried, and concentrated to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 2 h, J=8.8 Hz), 7.37 (d, 2H, J=8.0 Hz), 7.21 (t, 2H, J=8.8 Hz), 7.15 (d, 2H, J=8.0 Hz), 6.96 (t, 1H, J=7.2 Hz), 6.82 (d, 2H, J=7.2 Hz), 6.74 (d, 2H, J=8.8 Hz), 4.43, 4.39 (ABq, 2H, J=15.2 Hz), 4.22, 4.17 (ABq, 2H, J=7.2 Hz), 3.96 (t, 1H, J=6.4 Hz), 3.85-3.78 (m, 1H), 3.61-3.55 (m, 1H), 3.35 (t, 1H, J=8.8 Hz), 3.26, 3.12 (ABq, 2H, J=13.6 Hz), 3.16-3.07 (m, 2H), 2.99 (t, 1H, J=8.0 Hz), 2.26-2.19 (m, 1H), 1.90-1.83 (m, 1H), 1.39(s, 3H), 1.21 (t, 3H, J=7.2 Hz), 1.14 (t, 3H, J=7.2 Hz). MS [EI+] 599 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13](OC)=[O:14])=[O:6])[CH:2]=[CH2:3].[Li+].[BH4-]>C1COCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A solution of the ester 3 (19.5 g, 85 mmol) in THF (326 mL) was cooled to 0□C (ice/acetone) and treated with LiBH4 (2.78 g, 128 mmol) in portions. The reaction mixture was allowed to warm to room temperature and stirred under a nitrogen atmosphere for 2.5 hours at which time TLC (50% EtOAc/Petroleum Ether) revealed complete consumption of ester 3. The mixture was cooled to 0° C. and water (108 mL) was carefully added followed by 2 N HCl (54 mL). After evaporation of the THF in vacuo, the mixture was neutralised to pH 7 with 10 N NaOH and saturated with solid NaCl. The saturated aqueous solution was then extracted with EtOAc (5×100 mL), the combined organic layers washed with brine (200 mL), dried (MgSO4), filtered and evaporated in vacuo to furnish the pure diol 4 as a clear colourless oil (16.97 g, 99%): [α]24D=−57.0° (c=0.61, CHCl3); 1H NMR (270 MHz, CDCl3) δ 6.01-5.87 (m, 1H, NCO2CH2CH═CH2), 5.36-5.20 (m, 2H, NCO2CH2CH═CH2), 4.84 (br s, 1H, NCHCH2OH), 4.60 (d, 2H, J=5.31 Hz, NCO2CH2CH═CH2), 4.39 (br s, 1H, NCHCH2OH), 4.18-4.08 (m, 1H, 3.35, NCH2CHOH), 3.90-3.35 (m, 4H, NCH2CHOH, NCHCH2OH, and OH), 3.04 (brs, 1H, OH), 2.11-2.03 (m, 1H, NCH2CHOHCH2), 1.78-1.69 (m, 1H, NCH2CHOHCH2); 13C NMR (67.8 MHz, CDCl3) δ 157.1 (NC═O), 132.6 (NCO2CH2CH═CH2), 117.7 (NCO2CH2CH═CH2), 69.2 (NCH2CHOH), 66.4 and 66.2 (NCO2CH2CH═CH2 and NCHCH2OH), 59.2 (NCHCH2OH), 55.5 (NCH2CHOH), 37.3 (NCH2CHOHCH2); MS (EI), m/z (relative intensity) 201 (M+, 2), 170 (M-CH2OH, 100), 144 (M-OC3H5, 6), 126 (26), 108 (20), 68 (9); IR (Neat) 3394 (br, OH), 2946, 2870, 1679 (C═O), 1413, 1339, 1194, 1126, 1054, 980, 772 cm−1; exact mass calcd for C9H15NO4 m/e 201.1001, obsd m/e 201.1028
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:21](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.9 %

Procedure:
To a stirred solution of trans-1-tert-butoxycarbonyl-(2S)-hydroxymethyl-4-hydroxypyrrolidine (2.17 g, 10.0 mmol) and imidazole (2.04 g, 30.0 mmol) in DMF (50 ml) was added TBDPS-Cl (3.03 g, 11.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. Water was added thereto, and extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc(3:2, v/v) as eluent to give trans-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-hydroxypyrrolidine (1.5 g, 33%) as a white crystalline solid. 1H-NMR (CDCl3) δ 1.03 (s9H), 1.25 and 1.32 (each s, 9H), 1.90–2.10 (m, 1H), 2.30–2.40 (m, 1H), 3.40–3.80 (m, 3H), 3.95–4.15 (m, 2H), 4.45–4.55 (m, 1H), 7.37–7.39 (m, 6H), 7.63–7.64 (m, 4H).
Reaction SMILES: CS(Cl)(=O)=O.[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].O[C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:31][C:32]3[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=3)[CH:25]=2)=[C:19]([CH3:40])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:23][C:21]1[CH:22]=[C:17]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:18]=[C:19]([CH3:40])[C:20]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([CH:36]=[O:37])=[CH:38][CH:39]=2)[CH:25]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Reactant: O=C1CCCN1CCCO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(OCCCN2CCCC2=O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride was dropwise added to a mixture of 1-(3-hydroxypropyl)pyrrolidin-2-one, triethylamine and ethyl acetate under ice-cooling, followed by stirring at 0° C. for 2 hours to obtain a colorless oil. 4-[(4′-Hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]benzaldehyde, cesium carbonate and DMF were added to the resulting oil, followed by stirring with heating at 60° C. for 19 hours to obtain 4-({2′,6′-dimethyl-4′-[3-(2-oxopyrrolidin-1-yl)propoxy]biphenyl-3-yl}methoxy)benzaldehyde.