Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][C:33]1[C:34]([F:47])=[CH:35][C:36]([Br:46])=[C:37]([N:39]2[C:43](=[O:44])[N:42]([CH3:45])[N:41]=[N:40]2)[CH:38]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:32][C:33]3[C:34]([F:47])=[CH:35][C:36]([Br:46])=[C:37]([N:39]4[C:43](=[O:44])[N:42]([CH3:45])[N:41]=[N:40]4)[CH:38]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2
Reactant: Cn1nnn(-c2cc(N)c(F)cc2Br)c1=O
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2Br)c1=O
Temperature: 110 °C
Yield: 52.6 %

Procedure:
(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (1.4525 g. 4.86 mmol) and p-toluenesulfonic acid (1.7288 g, 9.09 mmol) were weighed out and added to a large reaction tube containing 1-(5-amino-2-bromo-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (2.10 g, 7.29 mmol). 42 mL isopropyl alcohol was added, and the tube was sealed and heated overnight at 110° C. The reaction was basified with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate. Product solution was filtered, concentrated onto a plug of silica, and purified by column chromatography. Pure fractions were combined, concentrated and dried under high vacuum to give 1.4063 g of the title compound (53% yield).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11]CCCCCCCCC)=[N+:2]=[N-:3].[N:22](CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7]([C:8]1[NH:22][CH:11]=[CH:10][CH:9]=1)=[O:21])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNC(=O)c1ccc[nH]1
Yield: 65.4 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.249 g, 1.17 mmol) was reacted with 2-azidoethanamine (0.101 g, 1.17 mmol) and triethylamine (0.237 g, 2.34 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-1H-pyrrole-2-carboxamide (0.137 g, 66%). 1H NMR (300 MHz, CD3OD) δ 6.88 (d, 1H), δ 6.77 (d, 1H), δ 6.14 (t, 1H), δ 3.46 (t, 2H), δ 3.37 (q, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 162.9, 125.6, 122.2, 121.9, 110.9, 109.2, 50.6, 38.9 ppm; HRMS (ESI) calcd for C7H9N5O (M+) 179.0807, found 179.0803.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])[N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]#[CH:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CN(C=O)C.[Cu]I>[CH2:11]([N:10]([CH2:14][CH2:15][CH3:16])[C:9](=[O:17])[NH:8][C:4]1[CH:3]=[C:2]([C:20]#[C:19][CH2:18][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH:7]=[CH:6][CH:5]=1)[CH2:12][CH3:13]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCCN(CCC)C(=O)Nc1cccc(Br)c1
Agent: [Cu]I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)Nc1cccc(C#CCNC(=O)OC(C)(C)C)c1
Temperature: 70 °C
Reaction time: 22 h

Procedure:
A solution of 3-(3-bromophenyl)-1,1-dipropylurea (24) (0.507 g, 1.70 mmol), tert-butyl prop-2-ynylcarbamate (15) (0.323 g, 2.12 mmol), tri-o-tolylphosphine (0.0342 g, 0.112 mmol) and Et3N (3.0 mL) in DMF was degassed by bubbling argon for 10 min, and applying vacuum/argon 3×. PdCl2(Ph3P)2 (0.0434 g, 0.062 mmol) followed by CuI (0.0263 g, 0.138 mmol) were added and the mixture was degassed by applying vacuum/argon 3×. The reaction mixture was stirred under argon at 70° C. for 22 hrs. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (10% to 50% EtOAc—hexanes gradient) gave tert-butyl 3-(3-(3,3-dipropylureido)phenyl)prop-2-ynylcarbamate (25) as a pale yellow solid. Yield (0.174 g, 28%); 1H NMR (400 MHz, DMSO-d6) δ 8.15 (br.s, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.42-7.46 (m, 1H), 7.31 (br.t, 1H), 7.17 (t, J=7.8 Hz, 1H), 6.89-6.93 (m, 1H), 3.93 (d, J=5.7 Hz, 2H), 3.21 (t, J=7.6 Hz, 4H), 1.47 (sextet, J=7.4 Hz, 4H), 1.32-1.38 (m, 9H), 0.82 (t, J=7.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:11])=[O:10].[CH3:37][O:38][CH2:39][CH2:40][OH:41]>>[C:35]([C:32]1([NH:31][C:29]([C@@H:14]2[CH2:13][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([O:41][CH2:40][CH2:39][O:38][CH3:37])=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)=[O:30])[CH2:34][CH2:33]1)#[N:36]
Reactant: COCCO
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Product: COCCOc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)N(c3cc(C)nn3C3CCOCC3)C2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 392, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide (example 464d) was reacted with 2-methoxyethanol (CAS Reg. No. 109-86-4) to give the title compound as colorless oil. MS (ESI): m/z=592.2 [M+H]+.
Reaction SMILES: [OH:1]O.[N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1>CC(O)=O>[N+:3]1([O-:1])[C:11]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1
Reactant: c1cnc2[nH]cnc2c1
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1c[nH]c2ncccc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Hydrogen peroxide (30 wt % solution in water, 38.0 ml, 372 mmol) was added to a suspension of 3H-imidazo[4,5-b]pyridine (4.93 g, 41.4 mmol) in AcOH (40 mL) at room temperature. The resulting reaction mixture was stirred at 80° C. for 3 h, cooled to RT and concentrated in vacuo to a volume ˜50 mL. Concentration to dryness was done using a stream of N2. The resulting residue was suspended in water (˜10 mL). Filtration afforded the title compound (4.61 g, 82.4% yield).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:3]1=2.[K+].[Br-]>>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:3]1=2
Reactant: N#Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [Br-]
Agent: [K+]
Product: N#Cc1ccc2c(c1)C(O)c1ccccc1CO2

Procedure:
In a similar manner as above, 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-carbonitrile XII was prepared from the oxepin-carbonitrile XI in a quantitative yield. IR spectrum (KBr tablet, cm-1): 2230, 1610, 1500, 1260, 1240, 1000; NMR spectrum (CDCl3 +d6DMSO, δ-value, ppm): 5.23(d, 1H), 5.72(d, 1H), 5.88(d, 1H), 6.15(d, 1H), 6.7-7.9(m, 7H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12]([C:14]1([CH:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:16][O:15]1)=[O:13]>C(Cl)Cl>[CH3:10][O:11][C:12]([C:14]1([CH:17]([F:7])[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:16][O:15]1)=[O:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)C1(C(O)CCCCOc2ccc(Cl)cc2)CO1
Solvent: ClCCl
Product: COC(=O)C1(C(F)CCCCOc2ccc(Cl)cc2)CO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of 967 mg (6 mmol, 733 μl) of diethylaminosulfur trifluoride in 25 ml of methylene chloride cooled to -78° C. under a nitrogen atmosphere is added dropwise a solution of 945 mg (3 mmol) of 2-[5-(4-chlorophenoxy)-1-hydroxypentyl]-2-oxiranecarboxylic acid methyl ester (isomer A) in 25 ml of methylene chloride over 30 minutes. The mixture is stirred at -78° C. for 30 minutes and then is allowed to come to room temperature. The mixture is stirred at room temperature for 1.5 hours, is quenched with brine and is extracted with ethyl ether. The combined ethereal extracts are dried over magnesium sulfate, filtered and rotoevaporated to give a crude solid. Trituration with cyclohexane:isopropyl ether and subsequent high vacuum drying affords 597 mg of the title compound (isomer A) (Rf 0.45 in hexane:ethyl ether (1:1)): m.p. 76°-78° C.; IR (KBr) γ1740, 1497, 1257, 832 and 758 cm-1 ; NMR (CDCl3) δ1.54-2.02 (6H, m), 3.10 (1H, dd, J=3, 6 Hz), 3.18 (1H, d, J=6 Hz), 3.80 (3H, s), 3.96 (2H, t, J=7 Hz), 5.19 (1H, ddd, JHF = 48 Hz, 10, 3 Hz), 6.85 (2H, d, J=7 Hz) and 7.27 (2H, d, J=7 Hz).
Reaction SMILES: Cl.[C:2]([CH:6]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[NH:7]1)([O:4][CH3:5])=[O:3].[C:13]([CH2:17][CH2:18][CH:19]([CH3:23])[C:20](O)=[O:21])([O:15][CH3:16])=[O:14].C(N1CCOCC1)C.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.O1CCCC1>[C:2]([CH:6]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[N:7]1[C:20](=[O:21])[CH:19]([CH3:23])[CH2:18][CH2:17][C:13]([O:15][CH3:16])=[O:14])([O:4][CH3:5])=[O:3]
Reactant: COC(=O)C1NC2CCC1C2
Reactant: COC(=O)CCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCC(C)C(=O)N1C2CCC(C2)C1C(=O)OC
Yield: 57.4 %

Procedure:
A mixture of 3.83 g (0.02 m) of 3-carbomethoxy-2-azabicyclo[2.2.1]heptane hydrochloride from Example 1, 3.29 g (0.02 m) of 4-carbomethoxy-2-methylbutanoic acid, 2.3 g of N-ethylmorpholine, 5.4 g of 1-hydroxybenzotriazole, 4.13 g of dicyclohexylcarbodiimide and 60 ml of dry tetrahydrofuran was prepared with cooling and stirring, then, allowed to stir at room temperature for 18 hours. The mixture was filtered. The filtrate was evaporated to give a syrup which was dissolved in ethyl acetate and washed with 10% acetic acid/water and water. A solid separated. The ethyl acetate extract was further washed with 5% sodium bicarbonate solution and brine, then, dried and evaporated under reduced pressure to give 3.41 g (57%) of 3-carbomethoxy-2-(4-carbomethoxy-2-methylbutanoyl)-2-azabicyclo[2.2.1]heptane, mE 297.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH3:5][N:6]([N:8]=[N:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15](OC)=[O:16])[CH3:7].O>C1COCC1>[CH3:7][N:6]([N:8]=[N:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([NH:4][CH2:3][CH2:1][OH:2])=[O:16])[CH3:5]
Reactant: COC(=O)c1sccc1N=NN(C)C
Reactant: NCCO
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1ccsc1C(=O)NCCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To an ice cold (0-5° C.) solution of ethanol amine (5 mL) in THF (5 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (500 mg) in THF (5 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and the solution was extracted with ethyl acetate (3×50 mL). The combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product, which was recrystallized from chloroform-hexane gave the product as a pale orange color solid (430 mg, 77%), mp 118-122° C. IR (neat) νmax, 3397, 3278, 2926, 1621, 1353, 1298, 1220, 1083, 1007, 882, 775 cm−1;
Reaction SMILES: CO[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[C:10]([NH2:14])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>CO>[N:4]1([CH2:3][NH:14][C:10](=[O:13])[CH:11]=[CH2:12])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9]
Reactant: C=CC(N)=O
Reactant: COCN1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CO
Product: C=CC(=O)NCN1CCCC1=O
Yield: 40 %

Procedure:
A mixture of 65.6 g of 1-methoxymethyl-2-pyrrolidone, 75.5 g of acrylarnide, 0.20 g of p-toluene sulfonic acid and 0.20 g of phenothiazine was stirred under N2 atmosphere at 150° C. for 1 hour, during which time the methanol was removed by distillation. The residue was cooled, and recrystallized from acetone to give the title compound in a yield of 40%. mp: 73-74° C.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:18]12CC(C=C1)C=[CH:19]2>O1CCOCC1>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][N:1]3[CH:19]=[CH:18][N:3]=[N:2]3)[O:9][C:8]2=[O:10])=[N:12][CH:13]=1
Reactant: C1=CC2C=CC1C2
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(Br)cn2)C(=O)O1
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(Br)cn1
Reaction time: 16 h
Yield: 71.6 %

Procedure:
(5R)-5-(Azidomethyl)-3-(5-bromopyrid-2-yl)-1,3-oxazolidin-2-one (5.60 g, 18.7 mM) was dissolved in 1,4-dioxane (12 ml). Bicyclo[2.2.1]hepta-2,5-diene (10.3 g, 112 mM) was added and the yellow solution was stirred at 100° for 16 hours. The brown solution was concentrated and the residue was purified by flash chromatography eluting with ethyl acetate. Relevant fractions were combined to give the desired product (4.36 g) as a beige solid.
Reaction SMILES: [F:1][C:2]1([F:40])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=5)[C:30]([O:32]C(C)(C)C)=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1>ClCCl.FC(F)(F)C(O)=O>[F:40][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=5)[C:30]([OH:32])=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC(C)(C)OC(=O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 92 %

Procedure:
tert-Butyl 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoate (603 mg, 1.11 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 3.5 hours before it was evaporated to dryness to yield 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid (499 mg, 75%) as the TFA salt. ESI-MS m/z calc. 488.1. found 489.1 (M+1)+. Retention time 2.06 minutes.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:16]([Cl:17])=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:18][CH3:19])[CH:9]=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[NH2:7][C:8]1[C:16]([Cl:17])=[CH:15][C:11]([CH2:12][OH:13])=[C:10]([O:18][CH3:19])[CH:9]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1CO
Yield: 224.6 %

Procedure:
To a suspension of lithium aluminum hydride (25.0 g, 116 mmol) in tetrahydrofuran (150 mL), 4-amino-5-chloro-2-methoxybenzoic acid (5 g, 28.0 mmol) was added in portions under ice-water cooling and the mixture was heated under reflux for 5 hours. Under ice-water cooling, a saturated aqueous solution of Rochelle salt was added to stop the reaction and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of Rochelle salt and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The solid obtained was washed with a mixed solvent of hexane-ethyl acetate (4:1), collected by filtration, and dried under reduced pressure to obtain 4-amino-5-chloro-2-methoxybenzyl alcohol (11.8 g)
Reaction SMILES: C(N(CCCC)[C@H:6]([CH3:15])[C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8])CCC.C(C1C=C(C=CC=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=O.C([Zn]CC)C.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1.CCCCCC>[OH:8][C@H:7]([C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][CH3:15]
Reactant: CC(C)(C)OC(=O)c1cccc(C=O)c1
Reactant: CCCCN(CCCC)[C@H](C)[C@@H](O)c1ccccc1
Agent: CC[Zn]CC
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC[C@H](O)c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 1950.8 %

Procedure:
To the (1S,2R)-2-di-n-butylamino-1-phenyl-1-propanol (200 mg) in toluene (7 ml) solution, tert-butyl 3-formylbenzoate (3 g) in hexane (7 ml) solution was added and the mixture was stirred at room temperature for 20 minutes. Next, diethylzinc in 1N hexane solution (33 ml) was added to the reaction solution under ice cooling and the mixture was stirred at that temperature for 18 hours. Saturated ammonium chloride aqueous solution was added to the reaction solution, the mixture was stirred at 20 minutes, and 1N hydrochloric acid was added. The obtained mixed solution was extracted with ethyl acetate. The organic layer was dried over with anhydrous sodium sulfate, then concentrated to obtain the title compound (3.5 g).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:13])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[S:5][C:4](=[O:14])[CH:3]=1.I[CH:16]([CH3:20])[CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:20][O:1][C:2]1[C:6]([CH3:13])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[S:5][C:4](=[O:14])[CH:3]=1
Reactant: CC(I)CCCl
Reactant: CCCCCCC1(C)SC(=O)C=C1O
Product: CCCCCCC1(C)SC(=O)C=C1OCCCCCl
Yield: 61.7 %

Procedure:
From 33 (36 mg, 0.17 mmol) and 3-iodo-1-chlorobutane (40 μL, 0.34 mmol) following general procedure H was obtained 42 (32 mg, 75%) after flash chromatography (20% EtOAc/Hexanes). 1H NMR (400 MHz, CDCl3) δ 0.86 (t, J=5.1 Hz, 3H), 1.09-1.14 (m, 1H), 1.25 (s, 6H), 1.44-1.53 (m, 1H), 1.63 (s, 3H), 1.77-1.85 (m, 2H), 1.90-2.00 (m, 4H), 3.59 (t, J=4.5 Hz, 2H), 3.95-3.99 (m, 2H), 5.28 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 13.7, 22.3, 25.1, 26.1, 26.4, 29.1, 29.1, 31.5, 39.0, 43.9, 59.5, 71.6, 101.5, 185.9, 192.9. IR (NaCl) 2927, 1683, 1607 cm−1. Analysis Calculated for C15H25C2S: C, 59.1; H, 8.27; Found: C, 59.3; H, 8.39.
Reaction SMILES: [CH2:1]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH:4]=C.[OH2:18]>C1COCC1.O.O=[Os](=O)(=O)=O>[C:12]1([C:10]2[CH:9]=[CH:8][N:7]=[C:6]([CH2:1][CH2:2][CH2:3][CH:4]=[O:18])[N:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O
Reactant: C=CCCCc1nccc(-c2ccccc2)n1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: O=CCCCc1nccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-penten-1-yl)-4-phenylpyrimidine (P5, 142 mg) in THF/H2O (5/1 mL) were added OsO4 (4% in water, 0.2 mL) and NaIO4 (404 mg). The solution was stirred at room temperature for 0.5 h. Water was then added and the mixture extracted with DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give 141 mg of the title compound as an oil, which was used in the subsequent step without further purification.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH:5]1[O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH:5]1[O:15][CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18]
Reactant: CCOC(=O)N1CCC(N=[N+]=[N-])C(OCC(=O)OC(C)(C)C)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCC(N)C(OCC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
Ethyl 4-azido-3-(2-tert-butoxy-2-oxoethoxy)piperidine-1-carboxylate (Intermediate 239, 1.75 g) was dissolved in THF (60 mL), followed by the addition of deionised water (5 mL) and PS-triphenylphosphine resin (10.6 g), and stirred at room temperature over the week-end. The reaction mixture was filtered, and the resin was rinsed repeatedly with MeOH and a 1:5 MeOH:DCM mixture, and the filtrate was concentrated in vacuo, yielding the title compound (1.20 g, 75%). MS (GC-EI)[(M)+]: 302 for C14H26N2O5.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:17])=[C:12]([Cl:25])[CH:11]=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:25][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][NH:1][S:29]([CH2:28][C:27]([F:34])([F:33])[F:26])(=[O:31])=[O:30])[CH:15]=[CH:14][C:13]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:17]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CN)cc1Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CNS(=O)(=O)CC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 148 (0.18 g, 0.71 mmol) was dissolved in dry pyridine (0.9 mL) and 2,2,2-trifluoroethanesulfonyl chloride (0.12 mL, 1.1 mmol) was added. The solution was stirred at room temperature for 1 h after which it was concentrated in vacuo. The oil was diluted with H2O and the water phase was extracted three times with EtOAc. The combined organic phases were washed with 10% aqueous NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:2 as the eluent to afford the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.I[CH2:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH2:16][CH3:17])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2cc(Br)ccc2c1
Yield: 97.3 %

Procedure:
A mixture of 6-bromo-2-naphthoic acid (6.18 g, 24.6 mmol), iodoethane (19.7 mL, 38.39 g, 246.1 mmol) and Cs2CO3 (12.03 g, 36.9 mmol) in acetonitrile (200 mL) under an atmosphere was heated to reflux overnight. The resulting mixture was filtered and evaporated. The solid was dissolved in ethyl acetate and washed with water (4×), brine and dried (Mg2SO4). The mixture was filtered and evaporated to give 6.68 g of ethyl 6-bromo-2-naphthoate (97%) as a solid. 1H NMR (500 MHz; CDCl3): δ 1.45 (t, J=7.0 Hz, 3H); 4.44 (q, J=7.0 Hz, 2H); 7.61 (dd, J1=2.0 Hz, J2=9.0 Hz, 1H); 7.79 (d, J=8.5 Hz, 1H); 7.82 (d, J =9.0 Hz, 1H); 8.00–8.11 (m, 2H); 857 (brs, 1H),
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16](Cl)=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>CO.CCOCC>[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([N:6]2[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]2)=[O:17])=[CH:12][CH:11]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CO
Product: C[C@@H]1CN(C(=O)COc2ccc(Cl)cc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
To a solution of (cis)-2,6-dimethylpiperazine (0.115 g, 1.1 mmol) in methanol (35 mL) was added 4-chlorophenoxyacetyl chloride (0.205 g, 1.0 mmol, in solution of 6 mL of anhydrous ether). The resulting mixture was stirred at ambient temperature for 10 minutes and then triethylamine (0.10 mL, 0.72 mmol) was added. After 30 minutes, the mixture was concentrated in vacuo to afford an oily residue. This was taken up in ether and washed with saturated aqueous NaHCO3 solution, then brine. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford an oil. Purification by flash column chromatography afforded 0.202 g (80% yield) of (cis)-1-((4-chlorophenoxy)methyl)carbonyl-3,5-dimethylpiperazine, a compound of formula (K), as a clear, colorless oil; NMR (CDCl3) 7.3 (d, 2), 6.9 (d, 2), 4.7 (d,1), 4.6 (d,1), 4.4 (d,1), 3.8 (d,1), 2.7 (m, 3), 2.2 (t, 1), 1.1 (m, 6) ppm.