Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].Cl.[NH2:33][CH2:34][CH2:35][SH:36].C(N(CC)CC)C.O>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]/[NH:33][CH2:34][CH2:35][SH:36])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: NCCS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC[C@H]1OC(=O)/C(=C\NCCS)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 32 mg (0.278 mmol) 2-amino-ethanethiol hydrochloride and triethylamine (45 μL, 0.325 mmol). The reaction mixture is stirred at room temperature for 4 h. Water is added and the CH2Cl2 is removed, filtered through a plug of Kimwipe tissue and concentrated in vacuo to give a yellow foam. MS (ESI) m/z 508.5 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[CH3:20][SiH:21]([CH3:26])[O:22][SiH:23]([CH3:25])[CH3:24].[C:27]1(C)C=CC=CC=1>>[CH3:20][Si:21]([CH2:27][CH2:4][CH2:3][CH2:2][CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)([CH3:26])[O:22][SiH:23]([CH3:25])[CH3:24]
Reactant: C=CCCOc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: Cc1ccccc1
Reactant: C[SiH](C)O[SiH](C)C
Product: C[SiH](C)O[Si](C)(C)CCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
8.12 g (0.032 mol) of 4′-But-3-enyloxy-biphenyl-4-carbonitrile is dissolved in 80 mL of dry toluene and 21.50 g (0.16 mol) of 1,1,3,3-Tetramethyl-disiloxane is added. Dry air bubbled through the solution for 2 min and few drops of platinium(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex in xylene are added. After stirring at room temperature for 20 h with exclusion of moisture, the solvent and excess of 1,1,3,3-Tetramethyl-disiloxane are distilled off under reduced pressure. The residue purified by column chromatography on silica gel using a mixture of CH2Cl2/pentane (75/25) as eluent gives a colourless oil (10.67 g, 84% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].N[C:20](N)=[S:21].[OH-:23].[K+]>C(O)C>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:4][CH2:3][CH2:2][S:21][CH2:20][CH2:3][CH2:4][CH2:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:23])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:18])[CH3:11]
Reactant: CCOC(=O)C(C)(CCCCBr)c1ccccc1
Reactant: NC(N)=S
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(CCCCSCCCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A solution of ethyl 6-bromo-2-methyl-2-phenyl-hexanoate (18.5 g, 59.0 mmol), thiourea (7.0 g, 91.0 mmol), and potassium hydroxide (6.1 g, 92.0 mmol) in ethanol (200 mL) was heated to 40-50° C. overnight. The mixture was cooled to rt, poured into an ice/water/HCl mixture (150 g/150 mL/150 mL), and stirred for 20 min. The mixture was extracted with dichloromethane (4′ 60 mL) and the combined organic layers were washed with sat. NaHCO3 solution (100 mL) and sat. NH4Cl solution (100 mL). The dichloromethane solution was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexanes/ethyl acetate=10/1) to give 6-(5-ethoxycarbonyl-5-phenylhexylsulfanyl)-2-methyl-2-phenyl-hexanoic acid ethyl ester (12.5 g, 85%) as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): d (ppm): 7.42-7.15 (m, 10H), 4.20-4.05 (q, 4H, J=7.1 Hz), 2.44 (t, J=7.6 Hz, 4H), 2.15-1.95 (m, 2H), 1.95-1.75 (m, 2H), 1.62-1.40 (m, 10H), 1.35-1.10 (m, 4H), 1.18 (t, 6H, J=7.1 Hz). 13C NMR (75 MHz, CDCl3/TMS): d (ppm): 176.06, 143.89, 128.25, 126.52, 125.84, 60.65, 50.04, 38.77, 31.80, 30.11, 24.06, 22.61, 14.01. HRMS (LSIMS, nba): Calcd. for C30H43O4S1 (MH+): 499.2882, found 499.2868.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:11]2[CH:10]=[C:9]([OH:17])[CH:8]=[CH:7][C:6]=2[CH2:5][C@@H:4]1[O:18][CH3:19].C[O:21][C:22](=[O:34])[C@H:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:24][CH:25]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CCOC(C)=O>[CH:28]1([CH2:27][C@H:23]([CH2:24][CH2:25][NH:2][C@@H:3]2[C@@H:4]([O:18][CH3:19])[CH2:5][C:6]3[C:11](=[CH:10][C:9]([OH:17])=[CH:8][CH:7]=3)[C:12]2([CH2:15][CH3:16])[CH2:13][CH3:14])[C:22]([OH:34])=[O:21])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC(=O)[C@@H](CC=O)CC1CCCCC1
Reactant: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1NCC[C@@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125.8 %

Procedure:
(6S,7S)-7-Amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ol hydrochloride salt (100 mg, 0.35 mmol), (R)-2-cyclohexylmethyl-4-oxo-butyric acid methyl ester (90 mg, 0.42 mmol) and triethylamine (35 mg, 0.035 mmol) were dissolved in dichloromethane (2.0 mL) and stirred at room temperature for 30 min. Sodium triacetoxyborohydride (1.03 g, 4.85 mmol) was added and the reaction was monitored by HPLC. After 3 h, additional (R)-2-cyclohexylmethyl-4-oxo-butyric acid methyl ester (20 mg, 0.1 mmol) and sodium triacetoxyborohydride (30 mg, 0.14 mmol) were added. Thirty minutes after the last addition, EtOAc (15 mL) was added and the mixture was washed with 5% aqueous sodium carbonate (2×5 mL) and saturated sodium chloride (5 mL). The organic layer was dried with Na2SO4) and concentrated to give the title compound (190 mg). (m/z): [M+H]+ calcd for C27H43NO4, 446.33; found, 446.6.
Reaction SMILES: CCCCCCCCCCCCCCC.C[OH:17].[C:18]([N:21]1[CH2:25][CH2:24][CH:23]=[CH:22]1)(=[O:20])[CH3:19].[O:26]1[CH2:30]CC[CH2:27]1>>[CH3:27][O:26][C:30](=[O:17])[C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)N1C=CCC1
Reactant: C1CCOC1
Reactant: CO
Agent: CCCCCCCCCCCCCCC
Product: COC(=O)[C@@H]1CCCN1C(C)=O
Temperature: 100 °C
Reaction time: 21.75 h
Yield: 4.1 %

Procedure:
A 70 ml stainless steel high pressure reactor having a Pyrex glass liner and a magnetic stir bar was charged with 5 mL of tetrahydrofuran, 0.5 mmol of n-pentadecane internal standard, 0.5 mmol of CH3OH, 10.0 mg of Co2 (CO)6 (PPh3)2, and 55.0 mg of N-acetyl-2-pyrroline. The reactor was pressurized with 1320 psi of CO and 300 psi of H2 at room temperature, and the reaction mixture was stirred at 100° C. for 21.75 hours. Thereafter, the reactor was cooled to room temperature and vented to atmospheric pressure. The product mixture was analyzed by gas chromatography, and the analysis indicated 76.6% conversion of N-acetyl-2-pyrroline and 4.1% yield of N-acetylproline methyl ester.
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:36])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:25][CH2:24]1)=[O:36]
Reactant: COc1ccccc1CC(=O)C1CCN(Cc2nccnc2OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccccc1CC(=O)C1CCN(Cc2ncc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
After adding 2 ml of 4N hydrogen chloride/ethyl acetate to the obtained 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-methoxyphenyl)ethanone, the mixture was stirred overnight at room temperature. Aqueous 1N sodium hydroxide was added to the reaction solution for adjustment to pH 8, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added and the precipitate was filtered out to obtain the title compound (89 mg, 34% yield, 3 steps).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>O1CCCC1>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:23])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-3-(trifluoromethyl)benzoic acid (5.26 g, 23.4 mmol) in tetrahydrofuran (50 mL) were added N,N-dimethylformamide (40 μL) and oxalyl chloride (2.8 mL, 31.9 mmol), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give 2-chloro-3-(trifluoromethyl)benzoyl chloride. To a solution of 5-amino-2-methylphenol (2.62 g, 21.2 mmol) in tetrahydrofuran (20 mL) was added water (30 mL) in which sodium hydrogen carbonate (2.68 g, 31.9 mmol) has been suspended, and the mixture was vigorously stirred at room temperature. To the mixture was added dropwise a solution of 2-chloro-3-(trifluoromethyl)benzoyl chloride produced above in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, and filtered through a pad filled with silica gel. The solvent was concentrated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (6.37 g, 91%) as a pale-brown powder. The obtained compound was used for the next reaction without further purification operation.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])=[N+:2]=[N-:3].[CH2:17]([OH:20])[C:18]#[CH:19]>C1(C)C=CC=CC=1>[OH:20][CH2:17][C:18]1[N:1]([CH2:4][CH2:5][N:6]2[C:7](=[O:16])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]2=[O:15])[N:2]=[N:3][CH:19]=1
Reactant: [N-]=[N+]=NCCN1C(=O)c2ccccc2C1=O
Reactant: C#CCO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCn1nncc1CO
Temperature: 25 °C
Yield: 31.1 %

Procedure:
Heat a mixture of 2-(2-azidoethyl)isoindoline-1,3-dione (12 g, 55.5 mmol) and 2-propyn-1-ol (3.88 mL, 66.6 mmol) in toluene (50 mL) in a sealed reactor at 90° C. for 3 days. Cool to RT and collect the solid. Purify by column chromatography (DCM to 2% methanol in DCM) to give the title compound (first fraction) as a white solid (4.7 g, 31%). MS (ES) m/z 273 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:41])[CH2:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26]([NH:27][CH3:28])=[O:29])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:20])[NH:41][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:38][CH2:39][CH2:40]5)[CH:17]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC1(c2ccccc2)CCC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CCC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclobutylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid (0.070 g, 0.14 mmol) and 1-phenylcyclobutanamine hydrochloride (0.040 g, 0.20 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.21 (s, 1H), 8.90 (d, J=7.02 Hz, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.96-8.03 (m, 2H), 7.88-7.96 (m, 3H), 7.63 (t, J=7.63 Hz, 1H), 7.53 (d, J=7.63 Hz, 2H), 7.48 (dd, J=7.32, 1.83 Hz, 1H), 7.30-7.37 (m, 4H), 7.21 (t, J=7.32 Hz, 1H), 2.82 (d, J=4.58 Hz, 3H), 2.63-2.71 (m, 2H), 2.58 (ddd, J=12.13, 8.62, 6.10 Hz, 2H), 2.03-2.11 (m, 1H), 1.84-1.93 (m, 1H). LCMS: retention time: 3.225 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 u, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 519 (MH+).
Reaction SMILES: Cl[N:2]1[CH2:7][N:6]([NH:8][CH2:9][C:10]([CH3:28])([CH3:27])[CH2:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=2)[CH2:5][N:4]([NH:29][CH2:30][C:31]([CH3:49])([CH3:48])[CH2:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([OH:43])=[C:35]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:34]=2)[CH2:3]1.[CH2:50]([SH:62])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61].CC(C)=O.[OH-].[Na+]>O>[CH2:50]([S:62][N:2]1[CH2:7][N:6]([NH:8][CH2:9][C:10]([CH3:28])([CH3:27])[CH2:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=2)[CH2:5][N:4]([NH:29][CH2:30][C:31]([CH3:49])([CH3:48])[CH2:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([OH:43])=[C:35]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:34]=2)[CH2:3]1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CC(C)(CNN1CN(Cl)CN(NCC(C)(C)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCCSN1CN(NCC(C)(C)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CN(NCC(C)(C)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1
Reaction time: 5 h

Procedure:
10.0 g (0.014 mol) of 1-chloro-3,5-di-[3-(3,5-di-tert.butyl-4-hydroxyphenyl)-2,2-dimethylpropylamino]-s-triazine (the product of Example 64) and 2.91 g (0.044 mol) of dodecylmercaptan are initially introduced into 50 ml of acetone and 0.58 g (0.0144 mol) of sodium hydroxide, dissolved in 1 ml of water, is added at room temperature. The mixture is then heated to the point of reflux and is stirred at this temperature for 5 hours. It is then cooled, insoluble matter is filtered off and the filtrate is concentrated completely. The residue is purified through a silica gel column using toluene:methanol (98:2) as the migrating agent. The 1-dodecylmercapto-3,5-di-[3-(3,5-di-tert.butyl-4-hydroxyphenyl)-2,2-dimethylpropylamino]-s-triazine obtained in this way is produced as a yellowish resin. (Stabiliser No. 68).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14]>C(=O)([O-])[O-].[K+].[K+].CC(C)=O>[CH2:14]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C=O)ccc1OC
Yield: 88.5 %

Procedure:
Isovanillin (76 g) was dissolved in a stirred mixture of potassium carbonate (104 g) and acetone (450 mls) followed by the dropwise addition of allyl bromide (67 g) over ca. 20 mins. The mixture was refluxed for 5 hours, cooled and filtered. The solvent was removed from the filtrate under reduced pressure and the residue was distilled under vacuum to yield 3-allyloxy-4-methoxybenzaldehyde (85 g), b.p. 1.37-150° C. at 1.5 mbar.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23][CH3:24])[CH:21]=1)[NH:18][CH:17]=[CH:16]2.O[CH:26]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[CH:27]1[CH2:29][CH:28]1[C:30]#[N:31]>ClCCl>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23][CH3:24])[CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:26]([C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[CH:27]1[CH2:29][CH:28]1[C:30]#[N:31]
Reactant: CSCc1cc(F)cc2cc[nH]c12
Reactant: Cc1ccc(C(O)C2CC2C#N)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cc(F)cc2c(C(c3ccc(C)cc3)C3CC3C#N)c[nH]c12

Procedure:
130 mg (0.59 mmol) of indium(III) chloride and 0.05 ml (0.64 mmol) of trifluoroacetic acid were added to 104 mg (0.53 mmol) of the compound from Example 11A and 100 mg (0.53 mmol) of the compound from Example 158A in 6 ml of dichloromethane, and the mixture was stirred under reflux for 1 h. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 39.6 mg (20% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[Cl:36][C:37]([Cl:47])([O:39][C:40](=O)[O:41]C(Cl)(Cl)Cl)[Cl:38]>ClCCl>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][NH:2][C:40](=[O:41])[O:39][C:37]([Cl:47])([Cl:38])[Cl:36])=[C:7]([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH:8]=1)=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OC(Cl)(Cl)Cl)c(-c3ccnn3C)c2)c1

Procedure:
N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (80.0 mg, 1981 mmol), triethylamine (277 μl, 10 eq) and triphosgene (64.8 mg, 1.1 eq) were dissolved in 5 mL of dichloromethane and stirred under reflux for 5 mins. The solvent was removed under vacuum and 4 mL of ethyl acetate was added. It was divided in two and used immediately in the preparation of compound 5 and 7 without purification. LCMS m/z (%)=528 (M+H, 100).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:9]=1)[CH:3]=[O:4]
Reactant: CC(C)(CO)COCc1ccc(F)c(Cc2ccccc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C=O)COCc1ccc(F)c(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2,2-dimethyl-3-(3-benzyl-4-fluorobenzyloxy)-propan-1-ol (from the previous Example) in dichloromethane (15 cm3) was added dropwise to a stirred suspension of pyridinium chlorochromate (5.13 g) in dichloromethane (40 cm3) whilst the reaction temperature was maintained within the range 0°-5° C. When the addition was complete the mixture was allowed to warm to the ambient temperature (ca 25° C.) over a period of two hours, and left to stir for 14 hours. Diethyl ether was then added to the reaction mixture, and the whole was flushed through a plug of silica gel using diethyl ether as eluent. Evaporation of the solvent under reduced pressure gave a green oil which was subjected to column chromatography through silica gel using petroleum ether (boiling range 40°-60° C.) containing diethyl ether (10% by volume) as eluent, to give 2,2-dimethyl-3-(3-benzyl-4-fluorobenzyloxy)propan-1-al (1.40 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1.C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL) CHCl3 (40 mL) in a dry flask, under nitrogen. TEA (8.14 mL<58.4 mmol) is added and the mixture is heated to 50° C. for 4 h. The mixture is diluted with CHCl3 (60 mL), washed with 5% HCl (2×40 mL), dried over anhydrous MgSO4 and concentrated to a brown paste (8.31 g). The crude material is chromatographed over a standard 90 g Biotage column, eluting with 10% EtOAc/hexane (1 L) followed by 15% EtOAc/hexane (1 L). The appropriate fractions are combined and concentrated to afford 4.22 g (91%) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3SI+H1: 249.0947, found 249.0947.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=[O:8].BrCCOC1C=CC(OC)=C(OC)C=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=[O:8]
Reactant: COc1ccc(OCCOC(=O)C2CCCCN2C(=O)OC(C)(C)C)cc1OC
Agent: COc1ccc(OCCBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc(OCCOC(=O)C2CCCCN2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-tert-Butyl 2-(2-(3,4-dimethoxyphenoxy)ethyl) piperidine-1,2-dicarboxylate (456 mg, 1.1 mmol), prepared by reacting 1-tert-butyl-piperidine-1,2-dicarboxylate and 4-(2-bromoethoxy)-1,2-dimethoxybenzene in acetone in the presence of potassium carbonate, was dissolved in 10 ml 20% TFA in DCM and was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and used for next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH2:9])=O)[N:4]=[N:3]1.[BH4-].[Li+].[Cl-:12].[NH4+]>COCCOCCOC.CO>[ClH:12].[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][NH2:9])[N:4]=[N:3]1
Reactant: Cn1cc(C(N)=O)nn1
Reactant: [Cl-]
Agent: [BH4-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Solvent: COCCOCCOC
Product: Cl
Product: Cn1cc(CN)nn1
Temperature: 155 °C

Procedure:
A solution of 1-methyl-1H-1,2,3-triazole-4-carboxamide (Bull. Chem. Soc. Jap. (1972), 45(8), 2577-9) (0.050 g) in bis(2-methoxyethyl)ether (diglyme, 2 ml) was treated with lithium borohydride (0.0264 g) and heated to reflux (oil bath 155° C.). Methanol (0.18 ml) was added dropwise in two portions after 5 min and 35 min, and the mixture heated under reflux for 1.5 h with stirring under nitrogen. Saturated aqueous ammonium chloride (0.2 ml) was added dropwise to the cooled mixture, and the mixture was diluted with methanol (2 ml). The solution was applied directly to an Isolute SCX ion exchange cartridge (5 g) (pre-eluted with methanol) and eluted with methanol followed by 10% 0.880 ammonia in methanol. The ammonia in methanol fraction was evaporated to low volume (ca. 1 ml), acidified with 4N hydrogen chloride in 1,4-dioxane (1 ml), and evaporated to dryness in vacuo to give the title compound (0.030 g).