Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C@H:12]([C:13]([O-:15])=O)[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2].C([N:44]1[C@H:52]([C:53]([O-:55])=[O:54])CC(=O)C2C=CC=CC=2N(CC2C=CC=CC=2)C(=O)[C@H]1CC12CC3CC(CC(C3)C1)C2)(=O)C>>[C:1]([N:4]1[C@H:12]([C:13]([NH:44][CH2:52][C:53]([OH:55])=[O:54])=[O:15])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2Cl)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Product: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2Cl)c2ccccc2C(=O)C[C@H]1C(=O)NCC(=O)O

Procedure:
The compound was prepared by an identical route to that used to prepare example 22 except that (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-(2-chlorobenzyl)-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate was used in step a in place of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22](OC)OC)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7].[I-].[Na+].Cl[Si](Cl)(Cl)C.C(O)(=O)C.[NH2:43][CH2:44][C@@H:45]([C:47]1[CH:48]=[CH:49][C:50]([OH:58])=[C:51]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:52]=1)[OH:46].C([BH3-])#N.[Na+]>C(#N)C.CO.ClCCl>[F:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:43][CH2:44][C@H:45]([OH:46])[C:47]3[CH:48]=[CH:49][C:50]([OH:58])=[C:51]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:52]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: COC(Cc1ccc(NC2CCN(C(=O)NCc3cc(F)ccc3F)CC2)cc1)OC
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: C[Si](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [I-]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4cc(F)ccc4F)CC3)cc2)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.4 %

Procedure:
N-(2,5-Difluorobenzyl)-4-[4-(2,2-dimethoxyethyl)anilino]-1-piperidinecarboxamide (0.30 g, 0.69 mmol) was added to a pre-prepared mixture of sodium iodide (0.16 g, 1.03 mmol) and trichloro(methyl)silane (0.132 mL, 1.05 mmol) in anhydrous acetonitrile. The reaction was stirred at ambient temperature for 10 minutes. Dichloromethane was added and the reaction washed with 10% sodium thiosulfate solution, water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent partially removed in vacuo. The aldehyde solution was used directly and treated with methanol, acetic acid (0.062 mL, 1.02 mmol), N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (0.17 g, 0.69 mmol) followed by sodium cyanoborohydride (0.047 g, 0.764 mmol). The reaction was stirred at room temperature for 24 hours. The reaction was taken to dryness in vacuo, adsorbed onto silica and purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to yield the title compound (0.2 g, 0.32 mmol).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:17])[N:6]([CH2:18][CH2:19][CH3:20])[C:5](=[O:21])[CH:4]=1)[NH2:2].[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[CH3:22][NH:23][C:24]1[C:4]2[C:5](=[O:21])[N:6]([CH2:18][CH2:19][CH3:20])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:3]=2[NH:1][N:2]=1
Reactant: CCCn1c(=O)cc(NN)n(CCc2ccccc2)c1=O
Reactant: CN=C=S
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(CCc2ccccc2)c1=O
Reaction time: 15 h

Procedure:
A solution of 6-hydrazino-1-phenethyl-3-propyluracil (1.5 g, 5.2 mM) and methyl isothiocyanate (1.1 ml, 16 mM) in DMF (15 ml) was stirred at 60° C. for 2 hours and then at 120° C. for 15 hours. To the solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol afforded colorless crystals (0.7 g, 41%), m.p. 256°-258° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C>C1COCC1>[F:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([B:18]([OH:21])[OH:19])=[CH:2][CH:11]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(Br)cc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)c2ccccc12
Temperature: -78 °C
Yield: 78 %

Procedure:
A three-necked 250 mL flask fitted with two dropping funnels, magnetic stirring bar, and low-temperature thermometer was charged with 2-bromo-4fluoronaphthalene (10.9 g, 48.3 mmol) under nitrogen. Dry THF (100 mL) was added, and the solution was cooled to −78° C. To this solution was added n-butyllithium (33.2 mL of a 1.6 M solution, 53.1 mmol) dropwise through the first dropping funnel. The solution was stirred at −78° C. for 2 h whereupon trimethyl borate (6.0 g, 57.9 mmol) dissolved in 10 mL of dry THF was added dropwise through the second dropping funnel. The solution was allowed to warm to room temperature overnight. The reaction was quenched with dilute HCl (20%, 70 mL), and the reaction mixture was concentrated at 30° C. to 50% of its original volume by rotary evaporation and poured into H2O. The resulted biphasic solution was extracted with ethyl acetate (2×100 mL). The organic phases solution were washed twice with H2O and concentrated by rotary evaporation. The crude 4-fluoronaphthalen-1-ylboronic acid product was collected as a white solid powder by filtration and washed with hexane several times to remove impurity. It was dried at 20° C. under vacuum and used without further purification. It gave a white solid product in 78% yield (7.04 g, 37.7 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20]CC)=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([OH:20])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(N)c3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccnc(N)c2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(2-aminopyridin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (8 mL, 1:1) was added aqueous NaOH solution (200 mg in 2 mL of water). After stirring at room temperature for two hours, the reaction mixture was evaporated, acidified to pH 5 using 1 M HCl and then concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 12.3 (b, 1H), 9.30 (b, 1H), 7.87 (d, J=7.2 Hz, 1H), 7.69 (b, 2H), 7.25 (d, J=2 Hz, 1H), 7.13 (d, J=2 Hz, 1H), 6.59 (dd, J=7.2, 2.8 Hz, 1H), 6.00 (d, J=2.4 Hz, 1H), 5.49 (dd, J=9.6, 2.4 Hz, 1H), 3.05 (dd, J=15.6, 2.4 Hz, 1H), 2.28 (s, 3H), 2.08 (dd, J=15.2, 9.6 Hz, 1H). MS (ESI) m/z=313 [M−H]+.
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])=[CH:23][CH:22]=1)[CH:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6])C.O.[OH-].[Li+]>C1COCC1.O>[CH2:30]([NH:29][C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:7]([C:5](=[O:6])[C:4]([OH:42])=[O:3])[CH:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH3:9])=[CH:26][CH:25]=1)=[O:28])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CN(C(=O)C(=O)OCC)C(C)c2cccc3ccccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN(C(=O)C(=O)O)C(C)c2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The resin-bound ethyl{{4-[(dodecylamino)carbonyl]benzyl}[1-(1-naphthyl)ethyl]amino}-(oxo)acetate (described in step d, 0.0426 mmol) was swelled in THF (0.300 mL) for 15 min at rt. Lithium hydroxide monohydrate (36 mg, 0.852 mmol) diluted in H2O (0.060 mL) was added and the resulting reaction mixture was shaken 14 h at rt. The resin was washed successively with THF (1×15 min), H2O (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the resin-bound {{4-[(dodecylamino)carbonyl]benzyl}[1-(1-naphthyl)-ethyl]amino}(oxo)acetic acid which was used directly in the next step.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@@H:15]3[CH2:14][CH2:13][C:12](=[O:19])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:20].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.CCOC(C)=O.CCCCCC>C(O)C>[CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@@H:15]3[CH2:14][CH2:13][C:12](=[O:19])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:20]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Yield: 46.3 %

Procedure:
A solution of dione 53 (5.0 g, 18.36 mmol) and chloranil (5.4 g, 22 mmol) in dry ethanol (500 mL) was stirred at 60-65° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with dichloromethane. The solid was removed by filtration, and the filtrate was concentrated to give a brown gum. Chromatography (20% EtOAc/hexane) yielded crude dione 54 as a yellow solid (2.3 g, 46%): 1H NMR (300 MHz, CDCl3) δ0.94 (s, 3, CH3), 5.78 (s, 1), 6.25 (m, 2).
Reaction SMILES: COC1C=CC(CO[CH2:11][CH2:12][O:13][CH2:14][C@H:15]2[CH2:26][CH2:25][C:24]3[S:23][C:22]4[N:21]=[CH:20][N:19]=[C:18]([O:27][CH:28]5[CH2:33][CH2:32][CH:31]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]5)[C:17]=4[C:16]2=3)=CC=1.C(C1C(=O)C(Cl)=C(Cl)[C:47](=[O:48])C=1C#N)#N>ClCCl.O>[OH:48][CH2:47][CH2:11][CH2:12][O:13][CH2:14][C@H:15]1[CH2:26][CH2:25][C:24]2[S:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([O:27][CH:28]4[CH2:29][CH2:30][CH:31]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH2:32][CH2:33]4)[C:17]=3[C:16]1=2
Reactant: COc1ccc(COCCOC[C@H]2CCc3sc4ncnc(OC5CCC(N(C)C(=O)OC(C)(C)C)CC5)c4c32)cc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCCCO)CC4)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.3 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-([2-[(4-methoxyphenyl)methoxy]ethoxy]methyl)-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (700 mg, 1.17 mmol, 1.00 equiv) in dichloromethane (10 mL)/water (0.5 mL) was added DDQ (399 mg, 1.76 mmol, 1.50 equiv) and the resulting solution was stirred for 14 hrs at 25° C. under nitrogen. The resulting solution was diluted with water and extracted with 3×100 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-(4-[[(3S)-3-[(3-hydroxypropoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (370 mg, 64%) as a colorless oil. MS: m/z 478 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.Cl.[Cl:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH:17]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:10].[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[CH:15]=[N:14][CH:13]=[C:12]([CH2:11][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[CH3:3])[CH:17]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: Cc1ncc[nH]1
Reactant: ClCc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nccn1Cc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a suspension of sodium hydride (17 mg of a 55% dispersion in mineral oil, 0.39 mmol) in DMF (5 ml) was added 2-methylimidazole (32 mg, 0.39 mmol). This mixture was stirred for 1.5 h at 20° C. Following this, 3-chloromethyl-5-(3,4-dichloro-phenyl)-pyridine hydrochloride (1:1) (100 mg, 0.32 mmol) and triethylamine (78 mg, 0.78 mmol) were added and the mixture heated to 100° C. for 4 h. After cooling, the DMF was evaporated and the residue was directly chromatographed [silica, elution with CH2Cl2/(2M NH3 in MeOH)=85:15] to afford the free base of the title compound as a yellow oil. This material was dissolved in MeOH, cooled to 4° C. with stirring and treated with HCl/EtOH (1.46 M 1.1 eq) for 15 min. Evaporation of the solvent and drying under high vacuum at 50° C. for 2 h afforded the title compound (71 mg, 62%) as a light yellow solid. MS: m/e=317.1 (M+)
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[N+:38]([C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1)([O-:40])=[O:39]>C(Cl)(Cl)Cl>[C:24]([CH2:23][N:16]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:22][CH2:21][CH2:20][N:19]([CH2:45][C:44]2[CH:47]=[CH:48][C:41]([N+:38]([O-:40])=[O:39])=[CH:42][CH:43]=2)[CH2:18][CH2:17]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CN1CCCNCCN(CC(=O)OC(C)(C)C)CCCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CN1CCCN(Cc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OC(C)(C)C)CCCNCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.9 %

Procedure:
To a solution of compound (5) (1.27 g, 2.96 mmol) in dry CHCl3 (50 ml) were added triethylamine (1.21 ml, 0.90 g, 8.88 mmol) and 4-nitrobenzyl bromide (0.64 g, 2.96 mmol). After stirring at an ambient temperature for 10 hours, the solvent was removed under reduced pressure, and the residue was purified through column chromatography on alumina (basic). Extraction with a mixture of ethyl acetate and methanol (10:2) gave a purified clear oil, which was then solidified to obtain compound (7) (1.30 g, 78% yield). 1H NMR (500 MHz, CDCl3): δ 8.11-8.10 (dd, 2H), 7.55-7.53 (dd, 2H), 3.56 (s, 2H), 3.24 (s, 2H), 3.20-3.06 (m, 6H), 3.01 (brs, 2H), 2.70-2.58 (m, 4H), 2.54-2.42 (m, 4H), 2.39 (brs, 2H), 1.93 (brs, 2H), 1.75 (brs, 2H), 1.39-1.36 (dd, 18H); 13C NMR (125 MHz, CDCl3): δ 171.3, 170.5, 147.0, 146.6, 130.1, 123.3, 81.9, 81.2, 58.1, 56.4, 55.8, 54.9, 53.1, 51.6, 51.5, 51.2, 49.6, 48.5, 46.1, 28.0, 25.1, 22.7; HRMS (FAB) calculated for C29H50N5O6: 564.3761 [(M+H)+], measured value: 564.3757 [(M+H)+].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH2:23][O:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([CH2:32][CH2:33][C:34](OCC)=[O:35])=[C:27]([F:39])[C:26]=3[F:40])=[C:16]([C:19]([F:22])([F:21])[F:20])[S:17][CH:18]=2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15]([CH2:23][O:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([CH2:32][CH2:33][CH2:34][OH:35])=[C:27]([F:39])[C:26]=3[F:40])=[C:16]([C:19]([F:21])([F:22])[F:20])[S:17][CH:18]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3,5-trifluorophenyl)propanoate to give the desired product as off-white oil. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=7.5 Hz, 2H), 7.45 (s, 1H), 7.42 (d, J=8.0 Hz, 2H), 6.72 (m, 1H), 5.06 (s, 2H), 3.70 (t, J=9.0 Hz, 2H), 2.72 (t, J=9.1 Hz, 2H), 1.86 (m, 2H), 1.60 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O>C(O)C.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[N:16]1[CH:17]=[CH:18][C:13]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Brc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
A solution of 4-bromobenzeneboronic acid (2 g) in absolute ethanol (10 ml) was added slowly to a stirred mixture of 4-bromopyridine hydrochloride (1.96 g) in toluene (10 ml), 2M aqueous sodium carbonate solution (25 ml) and tetrakistriphenylphosphine palladium [0] (345 mg) under an atmosphere of argon. The mixture was heated to reflux and stirred at reflux for 3 hours. The mixture was cooled to ambient temperature and water (50 ml) was added. The resulting mixture was extracted with ethyl acetate (3×20 ml). The ethyl acetate extracts were combined and extracted with 2N aqueous hydrochloric acid. The acidic extract was cooled and basified by the addition of aqueous sodium hydroxide solution to give a pH of 9. The mixture was then extracted with ethyl acetate (5×50 ml). The ethyl acetate extracts were combined, dried (MgSO4) and evaporated to give 4-(pyrid-4-yl)bromobenzene as a solid (0.71 g), m.p. 123°-124° C.; microanalysis, found: C, 56.4; H, 3.4; N, 5.9%; C11H8BrN requires: C, 56.4; H, 3.4; N, 6.0%; m/z 234(M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]=[CH:9]N(C)C)=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2)=[O:16].C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:14]([C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)=[O:16])=[CH:9][N:8]=2)[N:7]=1
Reactant: CN(C)C=Nc1ccc(Cl)nn1
Reactant: O=C(CBr)c1ccc2ncccc2c1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12

Procedure:
A mixture of N′-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine (Stage 1.6, 2 g, 10.8 mmol), 2-bromo-1-quinolin-6-yl-ethanone (Stage 1.3, 3.36 g, 10.8 mmol) and triethylamine (1.1 g, 10.8 mmol) was stirred under reflux for 90 min. The reaction was allowed to cool and water (100 mL) was then added. The resulting red precipitate was filtered off to afford the title compound as a red solid (tR 1.2 min(conditions 1), MH+=309).
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.Br[C:15]1[CH:16]=[C:17]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:18]([Cl:21])=[N:19][CH:20]=1.C([Li])CCC>C1COCC1>[Cl:21][C:18]1[N:19]=[CH:20][C:15]([B:1]([OH:6])[OH:2])=[CH:16][C:17]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(B(O)O)cnc1Cl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
Triisopropyl borate (5.69 ml, 24.7 mmol) is added to a solution of N-(5-Bromo-2-chloro-pyridin-3-yl)-benzenesulfonamide (1 g, 2.87 mmol) in anhydrous THF (25 ml) under argon, and the resulting solution is cooled to −78° C. A 1.6 M solution of n-butyl lithium in hexanes (5.39 ml, 8.63 mmol) is added dropwise keeping the temperature below −70° C. The reaction is stirred at −78° C. for 50 minutes. The reaction is quenched with sat. aq. NaCl (20 ml) at −78° C. and then allowed to warm to room temperature and washed with EtOAc. The aqueous layer is concentrated in vacuo, and the residue is dissolved in 2.5M HCl, and the product is extracted into EtOAc, dried (MgSO4) and concentrated in vacuo to yield the title compound as a yellow oil. [M+H]+ 313.
Reaction SMILES: [Li+].[Br-].Br.CC[O:6][C:7]1[CH:12]=[CH:11][C:10]2[N:13]([CH3:21])[C@H:14]3[N:18]([CH3:19])[CH2:17][CH2:16][C@@:15]3([CH3:20])[C:9]=2[CH:8]=1.[Li+].[OH-]>O>[CH3:20][C@:15]12[C:9]3[CH:8]=[C:7]([OH:6])[CH:12]=[CH:11][C:10]=3[N:13]([CH3:21])[C@H:14]1[N:18]([CH3:19])[CH2:17][CH2:16]2
Reactant: CCOc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Agent: Br
Agent: [Br-]
Agent: [Li+]
Solvent: O
Product: CN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12
Temperature: 25 °C
Yield: 93.9 %

Procedure:
Add LiBr (80 g) to 48% aq HBr (40 mL) and water (40 mL) to make a clear solution. To this solution add (-) eserethole (21.31 g, 86.63 mmol) at room temperature under nitrogen with stirring. Heat (90°-100° C.) the brownish clear solution with an oil bath for 5.5 hours. Cool the dark greenish brown solution to room temperature and pour into ice-water (240 mL). To this solution was add 20% LiOH to pH 9-10. Extract the mixture with ethyl acetate (2×150 mL). Wash the combined ethyl acetate solution with brine, dry over potassium carbonate and filter. Concentrate the filtrate (to 100 mL) to provide a residue which contains eseroline (17.76 g, 95% yield, 98.8% purity). This solution was used immediately in the preparation of the title product.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[OH-].[Na+].O>C(O)C>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:18])[C:13]([OH:15])=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)C(C)c1ccc(CC=C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
24.6 g of ethyl α-(p-prenylphenyl)propionate was dissolved in 250 ml of ethanol, and a solution composed of 6.0 g of sodium hydroxide and 10 ml of water was added. The mixture was stirred overnight at room temperature, and concentrated. Water was added, and the mixtue was washed with diethyl ether. The resulting aqueous layer was acidified with 1 N hydrochloric acid, and extracted with diethyl ether. The extract was washed with an aqueous solution of sodium chloride, dried, concentrated and distilled to give 19.5 g of α-(p-prenylphenyl)propionic acid having the following boiling point and NMR spectrum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]4[CH2:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH2:16]4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC1Cc2ccccc2C1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC4Cc5ccccc5C4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-indan-2-yl-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.