Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[O:13].CC(=CCCC(C)=CCCC(C)=CC=O)C.CC(=CCCC(C)=CCC=C(C)C=C)C>>[OH:13][CH2:12][CH:11]=[C:10]([CH2:9][CH2:8][CH:7]=[C:6]([CH2:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])[CH3:15])[CH3:14]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Agent: C=CC(C)=CCC=C(C)CCC=C(C)C
Agent: CC(C)=CCCC(C)=CCCC(C)=CC=O
Product: CC(C)=CCCC(C)=CCCC(C)=CCO

Procedure:
Arctander "Perfume and Flavor Chemicals (Aroma Chemicals)" at monograph 1378 discloses "Farnesal", 2,6,10-trimethyl-2,6,10-dodecatrien-12-al to have a very mild, sweet oily, slightly woody, tenacious odor. On the other hand, Arctander also describes, at Monograph 1379, Farnesene, 2,6,10-trimethyl-2,6,9,11-dodecatetraene defined according to the structure: ##STR3## to have a very mild, sweet and warm, rather nondescript odor of good tenacity. Arctander further states that apart from some possible use in the reconstruction of certain essential oils, there is to the author's knowledge, very little, if any, use for this sesquiterpene in perfumery as such. Arctander further states that Farnesene having the structure: ##STR4## is produced by dehydration of Farnesol by heat with a potassium dehydrating agent or from Nerolidol by heat with acetic anhydride.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5](/[CH:6]=[CH:7]/[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13](Cl)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1/[CH:7]=[CH:6]/[C:5]1[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(/C=C/c2sccc2S(=O)(=O)Cl)cc1
Product: Cc1ccc(/C=C/c2sccc2S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 34 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-trans-styryl)thiophene-3-sulfonamide was prepared in the same manner as described in Example 10 by reaction of 2-(4-methyl-trans-styryl)thiophene-3-sulfonyl chloride with 5-amino-4-bromo-3-methylisoxazole. The crude product was purified by HPLC followed by crystallization resulting in a 34% yield, m.p. 101-105° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]=2[C@@H:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:34])=[O:33])[NH:5]1.I[CH2:37][C:38]#[N:39].C(#N)C>O1CCCC1>[C:38]([CH2:37][N:5]1[C@H:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:33])=[O:34])[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][C:8]=2[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[C:4]1=[O:3])#[N:39]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: N#CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C2=C(CCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC#N
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 12 mg, 0.30 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10A, 50 mg, 105 μmol) in tetrahydrofuran (3.0 mL). After 20 min, 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. After 2 h, a second portion of 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. After 2 h, a third portion of 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. The mixture is stirred over night, treated with acetonitrile and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 8 mg; ESI mass spectrum [M+H]+=515; Retention time HPLC: 1.01 min (Z018_504).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[C:10]([OH:13])(=O)[CH3:11].[CH3:14][C:15]([CH3:17])=O>O>[CH:15]([NH:1][C:2]1[CH:3]=[CH:6][C:11]([CH:10]=[O:13])=[C:8]([CH3:7])[CH:9]=1)([CH3:17])[CH3:14]
Reactant: CC(C)=O
Reactant: CC(=O)O
Reactant: Nc1ccccc1C=O
Solvent: O
Product: Cc1cc(NC(C)C)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In a 500-ml flask, place 46.05 g (0.2 m) of the blocked aminobenzaldehyde, 125 ml of acetic acid and 23.23 g (0.4 m) of acetone. Heat the mixture to 30 C. Add 11.78 g (0.2 m) of borane-dimethylamine complex slowly keeping the temperature below 50 C. Stir the mixture at 50 C. for 1 hour, and cool to room temperature. Add 200 ml of water and stir for 15 minutes. Collect solids, wash with water, and deliquor as much as possible. In a 500-ml flask, place the wet intermediate, 100 ml of methanol, and 60 g of 50% NaOH solution. Heat the mixture under reflux for 1 hour. Add 120 ml of hot water and distill off methanol till approximately 120 ml of distillate is collected and pot temperature reaches close to 100 C. Heat the mixture under reflux for 1 hour, and then cool to room temperature. Add 150 ml of propyl acetate, stir for 5 minutes, and let layers settle. Separate bottom water layer. Wash the propyl acetate solution with 100 ml of brine. Dry over magnesium sulfate and distill propyl acetate under a reduced pressure to a red viscous oil. Add 150 ml of heptanes with vigorous stirring. Stir the resulting slurry at room temperature for 45 minutes. Collect product, wash with heptanes, and dry to give 28.35 g (80%) of 4-isopropylamino-2-methylbenzaldehyde as yellow solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH:39]([OH:42])[CH2:40][CH3:41].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:42][CH:39]([CH2:40][CH3:41])[CH2:38][CH3:37])=[C:18]([CH3:24])[CH:17]=1
Reactant: CCC(O)CC
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCC(CC)OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 78.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-pentanol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (53 mg, yield 74%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:31]2[N:40]=[CH:39][C:38]3[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:37]=3)[C:32]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:28]=[C:22]3[CH:23]([CH3:27])[O:24][CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1)(=O)C.[OH-].[Li+].C(O)(C)C.C1COCC1>O>[C:41]([C:36]1[CH:37]=[C:38]2[C:33](=[C:34]([F:45])[CH:35]=1)[C:32](=[O:46])[N:31]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:28]=[C:22]5[CH:23]([CH3:27])[O:24][CH2:25][CH2:26][N:21]5[N:20]=4)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:40]=[CH:39]2)([CH3:42])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4C)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC1OCCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer was charged with 150i (48 mg, 1.0 eq., 0.077 mmol), lithium hydroxide (9.2 mg, 5.0 eq., 0.38 mmol), i-propanol/THF (4/4 mL), and water (1 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 150 as a yellow solid (6.8 mg, 15%). MS-ESI: [M+H]+ 585.8. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=4.5 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.03 (d, J=1.5 Hz, 1H), 7.59-7.53 (m, 4H), 7.47 (s, 1H), 5.72 (s, 1H), 4.82-4.78 (m, 1H), 4.52-4.49 (m, 2H), 4.33-4.30 (m, 1H), 4.30-4.27 (m, 1H), 4.02-3.98 (m, 3H), 3.73 (s, 3H), 1.54 (d, J=7.0 Hz, 3H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10]([O:12][C@H:13]3[CH2:16][C@H:15]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:14]3)=[N:9][C:8]([NH:22][C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)=[N:7][C:6]=2[N:5](COCC[Si](C)(C)C)[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:1]([C:3]1[C:11]2[C:10]([O:12][CH:13]3[CH2:16][CH:15]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:14]3)=[N:9][C:8]([NH:22][C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)=[N:7][C:6]=2[NH:5][CH:4]=1)#[N:2]
Reactant: C=CC(=O)N[C@H]1C[C@H](Oc2nc(Nc3cnn(C)c3)nc3c2c(C#N)cn3COCC[Si](C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C=CC(=O)NC1CC(Oc2nc(Nc3cnn(C)c3)nc3[nH]cc(C#N)c23)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of a 1:1 isomeric mixture of cis:trans N-{3-[(5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}prop-2-enamide in DCM (10 mL) was added TFA (1.9 mL). The solution was stirred at rt for 5 hrs and the solvents were removed. EtOH (20 mL), water (5 mL), and K2CO3 (424 mg) were added and the reaction mixture was stirred at rt for 30 min. The volatiles were removed to give a pale yellow solid. Water (20 mL) was added and the solid that precipitated out was collected by filtration, washed with water (5 mL) and dried to afford (185.6 mg, 80% yield) of N-[3-({5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)cyclobutyl]prop-2-enamide as a pale yellow solid (cis:trans mixture 1:1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66-9.47 (m, 1H) 8.58 (br. s., 1H) 7.84-8.08 (m, 1H) 7.74 (d, J=6.29 Hz, 1H) 7.48 (d, J=11.58 Hz, 1H) 5.99-6.34 (m, 2H) 5.40-5.71 (m, 2H) 4.06-5.20 (m, 2H) 3.71-3.90 (m, 3H) 2.90 (br. s., 1H) 2.12 (br. s., 1H). m/z (APCI+) for C18H18N8O2 379.1 (M+H)+. The cis/trans mixture (148 mg, 0.39 mmol) was subjected to further purification using supercritical fluid chromatography to separate the isomers: 64 mg of peak 1 and 60 mg of peak 2 was recovered from this separation. 1H NMR analysis of both peaks revealed that peak 1 corresponded to the cis isomer: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.29 (br. s., 1H) 9.16 (s, 1H) 8.50 (d, J=7.81 Hz, 1H) 7.90 (s, 1H) 7.86 (s, 1H) 7.54 (s, 1H) 6.01-6.27 (m, 2H) 5.53-5.70 (m, 1H) 5.13 (quin, J=6.92 Hz, 1H) 4.13 (sxt, J=7.76 Hz, 1H) 3.82 (s, 3H) 2.82-2.99 (m, 2H) 2.04-2.21 (m, 2H). m/z (APCI+) for C18H18N8O2 379.1 (M+H)+.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.C[O:13][C:14](=[O:18])[CH2:15][CH2:16]Br.O>CS(C)=O>[N:3]1([CH2:16][CH2:15][C:14]([OH:18])=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCn1ccc2ccccc21
Reaction time: 24 h

Procedure:
KOH (11.5 g, 0.2 mol.) was added to a solution of indole (5.0 g, 40.0 mmol.) and 3-bromopropionic acid methyl ester (4.37 ml, 40 mmol.) in DMSO (35 ml), and stirring was carried out for 24 h at RT. For working up, water (50 ml) was added to the mixture, washing was carried out with ether (5×20 ml), and the aqueous phase was adjusted to pH 4 with 1M HCl and extracted with ether (5×20 ml). The combined extracts were dried, filtered and concentrated. Chromatography with methanol yielded 3-indol-1-ylpropionic acid in a yield of 3.8 g (white solid, m.p. 54–56° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH2:22][CH3:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7]2.C1COCC1.CCO.O[Li].O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH2:22][CH3:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(OCC)cc(Cl)c2OC1C(F)(F)F
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(Cl)c2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
To a solution of the ester from Step 4 (250 mg, 0.713 mmole) in a 7:2:1 THF:EtOH:H2O mixture (10 mL) was added LiOH.H2O (44.9 mg, 1.07 mmole). The mixture was stirred room temperature for 15 minutes and then at 50° C. for 75 minutes. After standing at room temperature for 2.75 days, the solvent was removed in vacuo. The residue was redissolved in H2O (20 mL) and washed with ethyl ether (20 mL). The aqueous layer was concentrated to a volume of 5 mL and acidified with 1 N HCl. The resulting solid was filtered, washed with H2O and dried in vacuo to give 216 mg (94% yield) of the product as a yellow crystalline solid: ESHRMS m/z 321.0135 (M−H, C13H9ClF3O4, Calc'd 321.0136). 1H NMR (dmso-d6/300 MHz) 13.45 (brs, 1H), 7.88 (s, 1H), 7.13-7.16 (m, 2H), 6.02 (q, 1H, J=7.3 Hz), 4.03 (q, 2H, J=6.9 Hz), 1.32 (t, 3H, J=6.9 Hz).
Reaction SMILES: C1(S([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([CH:22]3[CH2:27][CH2:26][C:25]([CH2:29][OH:30])([OH:28])[CH2:24][CH2:23]3)[N:16]=[N:15]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>CO.O>[OH:30][CH2:29][C:25]1([OH:28])[CH2:24][CH2:23][CH:22]([N:17]2[C:18]3[C:14](=[CH:13][N:12]=[C:11]4[C:19]=3[CH:20]=[CH:21][NH:10]4)[N:15]=[N:16]2)[CH2:27][CH2:26]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c1ncc1nnn(C3CCC(O)(CO)CC3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OCC1(O)CCC(n2nnc3cnc4[nH]ccc4c32)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 11.8 %

Procedure:
To a solution of 4-(6-Benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-1-hydroxymethyl-cyclohexanol (200 mg, 0.47 mmol) in methanol (25 mL) was added a solution of sodium hydroxide (46.8 mg, 1.17 mmol) in water (5 mL), then the reaction mixture was stirred at 60° C. for 3 hours and neutralized with dilute hydrochloride acid until pH=7. The reaction mixture was purified by a reverse-phase preparatory HPLC (Column: Waters Xbridge C18 150*30 mm*5 um, 0% to 25%: acetonitrile+0.05% NH4OH in water, 10 min, 25 mL/min) to give 15.9 mg (39%) of 1-Hydroxymethyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanol, LCMS (Method K, ESI): RT=0.873 min, m+H=288.0; 1H NMR (400 MHz, DMSO-d6) δ: 8.97 (s, 1H), 7.57 (d, 1H), 6.96 (d, 1H), 5.14-5.07 (m, 1H), 4.62-4.57 (m, 1H), 4.31-4.25 (m, 1H), 3.52 (s, 3H), 2.25-2.18 (m, 2H), 2.18-2.15 (m, 2H), 1.93-1.90 (m, 2H), 1.62-1.51 (m, 2H); and 19.3 mg (39%) of 1-Hydroxymethyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanol, LCMS (Method K, ESI): RT=0.889 min, m+H=288.1; 1H NMR (400 MHz, DMSO-d6) δ: 12.32 (s, 1H), 8.96 (s, 1H), 7.57 (s, 1H), 7.17 (s, 1H), 5.01-4.98 (m, 1H), 4.67 (d, 1H), 4.38 (d, 2H), 2.54-2.46 (m, 2H), 1.88-1.63 (m, 6H).
Reaction SMILES: [BrH:1].C(O)(=O)C.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=2[Cl:6])[N:18]=1
Reactant: N#CSCC(=O)c1cccc(Cl)c1Cl
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: Clc1cccc(-c2csc(Br)n2)c1Cl
Temperature: 130 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A 25% hydrogen bromide/acetic acid (30 ml) solution was added to a solution of 2-(2,3-dichlorophenyl)-2-oxoethyl thiocyanate (3.10 g, 12.6 mmol) in acetic acid (30 ml), and the mixture was stirred at 130° C. for 2 hours. Water (60 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 3.68 g (94.6%) of the desired product as a solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[Si](OC[C:31]1[C:32]([C:37]2[CH:41]=[CH:40][N:39]([CH3:42])[N:38]=2)=[N:33][CH:34]=[CH:35][CH:36]=1)(C(C)(C)C)(C)C.Cl>CO>[CH3:21][N:20]1[C:16]([C:11]2[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:17][CH:18]=[N:19]1.[CH3:42][N:39]1[CH:40]=[CH:41][C:37]([C:32]2[CH:31]=[CH:36][C:35]([CH2:9][OH:8])=[CH:34][N:33]=2)=[N:38]1
Reactant: Cn1nccc1-c1ncccc1CO[Si](C)(C)C(C)(C)C
Reactant: Cn1ccc(-c2ncccc2CO[Si](C)(C)C(C)(C)C)n1
Agent: Cl
Solvent: CO
Product: Cn1ccc(-c2ccc(CO)cn2)n1
Product: Cn1nccc1-c1ncccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %
Yield: 72 %

Procedure:
To a mixture of 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine and 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-methyl-1H-pyrazol-3-yl)pyridine (420 mg, 1.38 mmol) in MeOH (20 mL) was added HCl (4 N, 2.0 mL). The mixture was stirred at rt for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO3(sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using EtOAc as eluent to give (2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (187 mg, 72%) and (2-(1-methyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol (55 mg, 21%) as white solids. Data for 2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol: 1H NMR (400 MHz; CDCl3) 8.58 (d, 1H), 7.91 (d, 1H), 7.46 (s, 1H), 7.30 (dd, 1H), 6.36 (s, 1H), 4.62 (d, 2H), 3.83 (s, 3H), 2.1 (t, 1H). LRMS (M+H+) m/z 190.1; data for (2-(1-methyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol: 1H NMR (400 MHz; CDCl3) 8.60 (d, 1H), 7.70 (d, 1H), 7.47 (s, 1H), 7.22 (dd, 1H), 6.99 (s, 1H), 5.91 (t, 1H), 4.68 (d, 2H), 4.01 (s, 3H). LRMS (M+H+) m/z 190.1
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@@H:22]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[C@@H:25]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:24]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@H:23]1[O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)C=C.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C.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:11][C:9]1[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]([C@H:22]2[C@H:23]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@@H:24]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:26]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[O:27]2)=[C:5]([OH:4])[CH:10]=1
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCCCCCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCCCCCO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of 5-(((2R,3R,4R,5S,6S)-6-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)pentan-1-ol (29, 479 mg, 0.584 mmol) from Step 2 in tetrahydrofuran (6 mL) were added sodium borohydride (177 mg, 4.668 mmol) and tetrakis(triphenylphosphine)palladium (67.5 mg, 0.058 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and quenched with saturated ammonium chloride, extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Flash chromatography on a Biotage® apparatus (silica gel, 10 to 50% tetrahydrofuran in hexanes gradient) gave the title compound (30, 459 mg, 0.58 mmol, 100%) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32]C(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.IC.N1C2C(=CC=CC=2)C=C1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:21][Si:22]([CH:23]([CH3:24])[CH3:25])([CH:26]([CH3:28])[CH3:27])[CH:29]([CH3:31])[CH3:30])[CH:16]=3)[N:11]([CH3:32])[C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[Si](Oc1ccc2[nH]c3c(c2c1)CCN(C(=O)OC(C)(C)C)C3)(C(C)C)C(C)C
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: c1ccc2[nH]ccc2c1
Solvent: CI
Solvent: CCOCC
Product: CC(C)[Si](Oc1ccc2c(c1)c1c(n2C)CN(C(=O)OC(C)(C)C)CC1)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
A solution of 6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester (175 mg, 0.39 mmol) in 3 mL of ethyl ether was added to a vigorously stirring solution of potassium tert-butoxide (263 mg) and 18-crown-6 (16 mg) in 10 mL ethyl ether. After 10 min, iodomethane (73 uL) in 0.5 mL of ethyl ether was added to the indole solution and the resulting mixture was stirred for 2 h. The solids were removed by filtration and the solvent was evaporated. Silica gel chromatography (10% ethyl acetate in hexanes) gave 9-methyl-6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester (75 mg).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.Cl[C:7]([O:9][CH3:10])=[O:8]>C(OCC)C>[CH3:10][O:9][C:7](=[O:8])[C:5]#[C:4][CH:1]1[CH2:3][CH2:2]1
Reactant: C#CC1CC1
Reactant: COC(=O)Cl
Solvent: CCOCC
Product: COC(=O)C#CC1CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of cyclopropyl acetylene (10.0 g, 148 mmol) in 50 mL of ethyl ether at −78° C. under argon was added methyllithiium (1.4 M in ethyl ether, 107 mL, 150 mmol). This solution was stirred at −78° C. for 1 h. Methyl chloroformate (12.0 mL, 154 mmol) was added. The reaction mixture was warmed to room temperature in 2 h and was quenched with water. The organic layer was separated. The aqueous layer was extracted with ethyl ether (50 mL×3). The combined organic layer was dried over sodium sulfate and evaporated to give cyclopropyl-propynoic acid methyl ester as a yellow oil (13.25 g, 72%).