Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[CH2:19][N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2([OH:25])[CH2:23][CH2:24][N:20]([CH2:19][C:18]3[CH:26]=[CH:27][CH:28]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:21]2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: COc1cccc(CN2CCC(=O)C2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(O)(c3ccc(Cl)cc3)C2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To 1-bromo-4-chlorobenzene (424 mg, 2.21 mmol) in tetrahydrofuran (10 mL), at −78° C., was added n-butyllithium (1.0 mL of a 2.5 M solution in hexanes, 2.4 mmol) dropwise. After 0.5 h, a solution of the ketone (500 mg, 2.43 mmol) from Step B above in tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 0.5 h and then warmed to 0° C. After 1.5 h, the reaction mixture was quenched with saturated ammonium chloride (5 mL) and warmed to ambient temperature. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated ammonium chloride (20 mL), water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (5% ethyl acetate/methylene chloride to 80% ethyl acetate/methylene chloride) gave 3-(4-chlorophenyl)-1-(3-methoxybenzyl)pyrrolidin-3-ol (250 mg, 35%) as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 7.50-7.42 (m, 2H), 7.34-7.29 (m, 2H), 7.27-7.22 (m, 1H), 6.96-6.91 (m, 2H), 6.83-6.80 (m, 1H), 3.82 (s, 3H), 3.57 (br s, 2H), 2.89-2.75 (m, 2H), 2.51-2.41 (m, 2H), 2.21-2.08 (m, 2H), 1.73-1.69 (m, 2H), 1.57 (s, 1H).
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[NH:6]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7]1>>[CH:1]1([CH2:4][N:6]2[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7]2)[CH2:3][CH2:2]1
Reactant: OCC1CCNC1
Reactant: O=CC1CC1
Product: OCC1CCN(CC2CC2)C1

Procedure:
In a manner similar to Preparation 8, react cyclopropanecarboxaldehyde with 3-pyrrolidinemethanol to obtain the title compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[N:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ncccn1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ncccn3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-N-methylpyrimidine-2-carboxamide.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][C:12]1([CH3:20])[CH2:17][CH:16]([CH3:18])[C:15](=[O:19])[CH:14]=[CH:13]1.[Cl-].[NH4+]>C(OCC)C>[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:15]2([OH:19])[CH:16]([CH3:18])[CH2:17][C:12]([CH3:20])([CH3:11])[CH:13]=[CH:14]2)=[CH:5][CH:4]=1
Reactant: CC1CC(C)(C)C=CC1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1CC(C)(C)C=CC1(O)Cc1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a slurry of magnesium turnings (66 g, 2.73 g.atoms) in diethyl ether (300 ml) was added a solution of 4-chlorobenzyl chloride (418 g, 2.6 moles) in diethyl ether (1500 ml) at such a rate as to maintain gentle reflux. After a further 30 minutes, a solution of 4,4,6-trimethylcyclohex-2- en-1-one (340 g, 2.46 moles) in diethyl ether (350 ml) was added, again maintaining a gentle reflux. After 1 hour the mixture was added into saturated aqueous ammonium chloride (4 liters) and the phases separated. The ether phase was back-washed with water (1 liter) and used directly in the next reaction. A small portion of 1-(4-chlorobenzyl)-4,4,6-trimethylcyclohex-2- en-1-ol was isolated for characterisation (gas chromatography analysis showed two isomers in approximately equal amounts).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([C@@H:42]5[CH2:46][CH2:45][CH2:44][N:43]5[CH3:47])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([C@@H:42]5[CH2:46][CH2:45][CH2:44][N:43]5[CH3:47])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17][S:58]([CH3:57])(=[O:60])=[O:59])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
A solution of Intermediate 149a (200 mg, 0.32 mmol) and DIPEA (164 μL, 0.95 mmol) in DCM (4 mL) was treated with methanesulfonyl chloride (32 μL, 0.41 mmol) and the reaction mixture was stirred at RT for 0.5 h. The mixture was diluted with DCM (5 mL) and washed with water (10 mL) and brine (10 mL). The layers were separated and the organic layer was passed through a phase separator and concentrated in vacuo to afford the title compound as a pale yellow solid (208 mg, 92%). LCMS (Method 3): Rt 3.02 min, in/z 713 [MH+].
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][N:28]=1)[CH:24]=O>>[Br:20][C:21]1[CH:22]=[C:23]([CH2:24][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:26]=[CH:27][N:28]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(Br)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 2-bromoisonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 404.91 g/mol.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>CO.[Pd]>[CH2:15]([N:17]([CH2:18][CH3:19])[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)[CH3:16]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 0.025 mol) and diethylamine (9.1 mL, 0.090 mol) in methanol (40 mL), 10% palladium on carbon (0.50 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 16 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure, then the residue was purified by chromatography on silica gel(dichloromethane/methanol) to afford tert-butyl 4-(diethylamino)piperidine-1-carboxylate as solid (6.1 g, y. 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:24]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([NH2:24])=[O:22])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CC#N
Product: NC(=O)C12CCC(NC(=O)OCc3ccccc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
4-Benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (998 mg) was suspended in acetonitrile (20 mL). While the suspension was chilled in an ice bath, N-hydroxybenzotriazole (605 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (757 mg) were sequentially added. The mixture was stirred at room temperature for 4 hours and was left overnight. Subsequently, 25% aqueous ammonia (1.80 mL) was added while the reaction vessel was chilled in an ice bath. The mixture was then stirred at room temperature for 1 hour. The insoluble material was filtered and washed sequentially with acetonitrile and dichloromethane. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluant:ethyl acetate) to give 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxamide (889 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:28]2[CH2:29][CH2:30][C:25]([OH:24])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26][CH2:27]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1C(=O)c2ccccc2C1C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
A solution of 3-(3,4-dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.112 g) in methanol (5 mL) was treated with 4-hydroxy-4-phenylpiperidine (0.057 g) and the pH was adjusted to 6 by adding acetic acid. After treating with sodium cyanoborohydride (0.030 g), the reaction mixture was stirred at ambient temperature for 16 hours, diluted with a saturated solution of sodium bicarbonate, and extracted with dichloromethane. The organic layers were dried and evaporated to obtain 3-[1-(3,4-dichlorophenyl)-3-(4-hydroxy-4-phenylpiperidino)propyl]-2-methyl-2,3-dihydroiso-indol-1-one as a foam (0.104 g). This material was transformed into the hydrochloride salt as follows. The above product was dissolved in dry dichloromethane (2 mL) and treated with HCl in ether (2 mL). The resulting solution was diluted with anhydrous ether, stirred for 2 hours and the resulting precipitate was collected to afford the title compound (0.075 g); mp 160° C. (dec); MS: m/z=509(M+1); NMR: 1.79 (broad,2), 3.32 (s,3), 3.75 (broad,1), 4.88 (m,1), 5.44 (s,1), 6.80-7.95 (m,12). Analysis for C29H30Cl2N2O2.HCl.0.5 H2O: Calculated: C, 62.76; H, 5.81; N, 5.13; Found: C, 62.79; H, 5.89; N, 4.89.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]1[C:17]2[C:18]3[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=3[S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:16]=2[CH2:15][CH2:14][NH:13][C:12]1=O.[H-].[Al+3].[H-].[H-]>O.C(OCC)C>[CH2:11]1[C:17]2[C:18]3[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=3[S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:16]=2[CH2:15][CH2:14][NH:13][CH2:12]1
Reactant: O=C1CC2=C(CCN1)c1ccccc1Sc1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: c1ccc2c(c1)Sc1ccccc1C1=C2CCNCC1
Temperature: 0 °C

Procedure:
With stirring and excluding moisture, a suspension of 1.14 g (0.03 mole) of lithium aluminium hydride in 75 ml of abs. diethyl ether is introduced slowly in a nitrogen atmosphere to an ice-cooled solution of 4 g (0.03 mole) of aluminium chloride in 100 ml of abs. diethyl ether in such a manner that the reaction temperature does not exceed 5° C. Thereafter a suspension of 2.93 g (0.01 mole) of 1,3,4,5-tetrahydro-2H-dibenzo[2,3:6,7]thiepino[4,5-d]azepine-2-one in 50 ml of abs. diethyl ether is added and the mixture is refluxed for 24 hours. After cooling to 0°-5° C., excess aluminium hydride is decomposed cautiously by the dropwise addition of 10 ml of water. The organic phase is then separated, washed with two 30 ml portions of water, dried over sodium sulphate and concentrated, to give 2,3,4,5-tetrahydro-1H-dibenzo[2,3:6,7]thiepino[4,5-d]azepine as residue, which melts at 142°-143° C. after recrystallisation from methanol. Melting point of the methanesulphonate: 305°-307° C.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)#[N:39].Cl>CN(C)C=O>[CH2:1]([N:8]([C@@H:9]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([C:38]#[N:39])=[CH:41][CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1cccc(OC[C@@H](CC(=O)OCc2ccccc2)NCc2ccccc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)N(Cc2ccccc2)[C@@H](COc2cccc(C#N)c2)CC(=O)OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
190 mg (0.47 mmol) of benzyl 3-(3R)-benzylamino-4-(3-cyanophenoxy)butyrate and 153 mg of triethylamine were stirred in 5 ml of dimethylformamide, and 70 mg (0.47 mmol) of 4-cyanobenzoyl chloride was added thereto under cooling with ice and stirred for 3 hours. 1 N hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The extract was washed with 1 N sodium hydroxide and saturated saline and dried over magnesium sulfate anhydride, and the solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[OH:35][C:36]1([C@@H:42]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][C:53]([F:56])([F:55])[F:54])[CH:47]=2)[C:43]([OH:45])=O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[CH3:57][C@H:58]1[CH2:63][NH:62][CH2:61][C@@H:60]([CH3:64])[NH:59]1>C(Cl)Cl>[CH3:57][CH:58]1[NH:59][CH:60]([CH3:64])[CH2:61][N:62]([C:43](=[O:45])[C@@H:42]([C:36]2([OH:35])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)[C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][C:53]([F:56])([F:54])[F:55])[CH:47]=2)[CH2:63]1
Reactant: O=C(O)[C@H](c1cccc(OC(F)(F)F)c1)C1(O)CCCCC1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN(C(=O)[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CC(C)N1
Reaction time: 18 h
Yield: 93.2 %

Procedure:
In one experiment, (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (41.73 g, 94.35 mmol) and triethylamine (88 mL, 630 mmol) were added to a mixture of (R)-2-(1-hydroxycyclohexyl)-2-(3-(trifluoromethoxy)phenyl)acetic acid (20.0 g, 62.9 mmol) and cis-2,6-dimethylpiperazine (7.17 g, 62.9 mmol) in methylene chloride (150 mL) at RT. After stirring for 18 h, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (50 to 100% ethyl acetate in heptane) to afford 1-(3,5-Dimethyl-piperazin-1-yl)-2-(R)-(1-hydroxy-cyclohexyl)-2-(3-trifluoromethoxy-phenyl)-ethanone (24.3 g, 93%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[CH:15][N:14]=1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CCCCCC.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.C(#N)C>[CH3:12][C:13]1[C:18]([C:2]2[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[CH:4][N:3]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Cc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)c1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ncccc1-c1cc(C(C)(C)C)ncn1
Yield: 92 %

Procedure:
Next, 2.0 g of 4-chloro-6-tert-butylpyrimidine obtained in Step 2, 3.0 g of 2-methylpyridine-3-boronic acid pinacol ester, 17 mL of 1M aqueous solution of potassium acetate, 17 mL of 1M aqueous solution of sodium carbonate, and 40 mL of acetonitrile were put in a 100 mL round-bottom flask, and the air in the flask was replaced with argon. To this mixture, 0.78 g of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was irradiated with microwaves under conditions of 100° C. and 100 W for 1 hour to cause a reaction. This reaction mixture was extracted with ethyl acetate, and washing with saturated brine was performed. Anhydrous magnesium sulfate was added to the obtained solution of the extract for drying, and the resulting mixture was gravity-filtered to give a filtrate. The resulting filtrate was dissolved in a mixed solvent of ethyl acetate and hexane, and the mixture was filtered through Celite, alumina, and Celite. The resulting filtrate was purified by silica gel column chromatography. As a developing solvent, a mixed solvent of hexane and ethyl acetate in a ratio of 3:2 (v/v) was used. The obtained fractions were condensed to give an oily substance. This oily substance was dissolved in a mixed solvent of hexane and ethyl acetate, and the solution was filtered through a filter aid in which Celite, alumina, and Celite were stacked in this order. The resulting filtrate was condensed to give 4-(2-methylpyridin-3-yl)-6-tert-butylpyrimidine (abbreviation: HtBumpypm) (light-yellow oily substance, yield of 92%). A synthetic scheme of Step 3 is shown in (a-3) below.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC([O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][C:23]#[C:24][CH:25]([O:27]C(=O)C1C=CC=CC=1)[CH3:26])C)C.C([O-])(O)=O.[Na+]>CO>[CH2:18]([OH:17])[CH2:19][C:20]#[C:21][CH2:22][C:23]#[C:24][CH:25]([OH:27])[CH3:26]
Reactant: CCOC(C)OCCC#CCC#CC(C)OC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(O)C#CCC#CCCO
Reaction time: 3 h

Procedure:
A mixture of crude I in about 100 mL of methanol was treated with approximately 0.3 g of p-toluenesulfonic acid. After about 3 hours TLC analysis indicated almost no starting material remained. GC/MS analysis showed one long retention time component (>95%) MS (rel. intensity) 256 (0.5, M+), 255 (3), 226 (1), 134 (5), 133 (2), 105 (100), 91 (12), 77 (35), and 51 (20). This mixture was treated with about 5 mL of saturated NaHCO3, and the solvent was removed in vacuo. The residue was taken up in ether and purified through a short silica gel (hexane/ ether approximately 9:1) column to provide approximately 2.7 g of unstable 3,6-nonadiyn-1,8-diol, 8-benzoate. A mixture of approximately 1.25 g of this material in about 60 mL of ethanol containing approximately 0.32 g of quinoline and approximately 180 mg of lindlar catalyst was hydrogenated at atmospheric pressure until hydrogen uptake ceased. After about 2 hours, approximately 100 mg of additional catalyst was added and the reaction was continued until hydrogen uptake ceased (Mori, K, and Ebata, T., Tetrahedron, Volume 42, 3471,1986; herein incorporated by reference in its entirety). GC/MS analysis showed one major long retention time component: MS (rel. intensity) 260 (1, M+), 229 (1), 138 (15), 123 (2), 105 (100), 93 (18), 91 (15), 79 (45), and 77 (50). The product was isolated by filtration through celite and removal of the solvent in vacuo. The residue was taken up in ether, washed with dilute HCl, and brine, and dried over MgSO4. The infrared spectrum of a sample of this material isolated by preparative gas chromatography showed important absorptions at 3433 (br), 3053, 3012, 1712, 1602, 1580, 1450, 1268, 1108, 1043, and 709cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22]([O:29][CH2:30][CH:31](OS(C1C=C(Cl)C=CC=1Cl)(=O)=O)[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C=O.C(OCC)(=O)C.O>[CH2:22]([O:29][CH2:30][CH:31]([CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[O:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(OC(COCc1ccccc1)COCc1ccccc1)c1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC(COCc2ccccc2)COCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
To a stirred solution of (R)-tert-butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (1.0 g, 3.74 mmol) in dry N,N-dimethylformamide (20 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (60% suspension in mineral oil) (0.33 g, 8.23 mmol) and the mixture stirred at 0° C. for 15 minutes. 2,5-dichloro-benzenesulfonic acid 2-benzyloxy-1-benzyloxymethyl-ethyl ester (2.20 g, 4.57 mmol) was added to the reaction mixture to form a yellow solution which was stirred at ambient temperature for 5 minutes before warming to 100° C. for 10 minutes. The reaction mixture which by now contained a heavy precipitate was cooled to ambient temperature, diluted with ethyl acetate, cooled to 0° C. and treated with an equal volume of water. The stirred mixture was acidified to pH≈4 with 1 M aqueous hydrochloric acid. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water (three times), dried over sodium sulfate, filtered through a thin pad of silica gel and concentrated in vacuo to give (R)-[4-(2-benzyloxy-1-benzyloxymethyl-ethoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid (1.20 g, 80%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].S(=O)(=O)(O)O>>[C:9]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CCCCCCC
Reactant: C=CC(=O)O
Agent: O=S(=O)(O)O
Product: C=CC(=O)OCCCCCCCC

Procedure:
To 1.00 g (0.00891 mole, 1 eq) of 1-octene heated to 50° C. was added a solution of 0.706 g (0.00980 mole, 1.1 eq) of acrylic acid and 2.00 g of a 96 wt-% solution of sulfuric acid (18 M, 0.0196 mole, 2.2 eq). After 15 minutes at 70° C. all the olefin was consumed but only 30% of the product was the desired acrylate.