Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C:15](OC)=[O:16]>C1(C)C=CC=CC=1>[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[CH:25]([CH3:26])[CH3:27])[C:15]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:16]
Reactant: COC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65.2 %

Procedure:
Trimethylaluminium (2M in toluene) (8.97 ml, 17.94 mmol) was added to 5-methylpyridin-2-amine (1.940 g, 17.94 mmol) in toluene (70 ml) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-methyl 2-hydroxy-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (3.0 g, 8.97 mmol) in toluene (20 ml) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 5 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organics were dried (MgSO4) filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (2.40 g, 65.2%). 1H NMR (400 MHz, CDCl3) δ 1.03-1.15 (24H, m), 2.29 (3H, s), 3.60-3.68 (3H, m), 3.82-3.86 (1H, m), 3.98-4.02 (1H, m), 4.14-4.15 (1H, m), 4.30-4.34 (1H, m), 7.49-7.52 (1H, m), 8.11-8.13 (2H, m), 9.14 (1H, s); m/z (ES+) (M+H)+=411.44; HPLC tR=3.46 min.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([C:22]([OH:24])=[O:23])=[CH:14]1.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>C1COCC1.CCCCCC>[CH3:25][Si:26]([C:14]1[O:13][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]=1[C:22]([OH:24])=[O:23])([CH3:28])[CH3:27]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1coc2ccccc12
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1oc2ccccc2c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (4 mL) in 20 mL THF at -60° C. was added 2.5 M of n-BuLi in hexane (17 mL), and the solution was stirred at between -20 and -60° C. for 1 h. To this, a solution of 3-benzofurancarboxylic acid (2.6 g) in 30 mL THF was added at <-70° C. After 1 h, TMSCl (7 mL) was added at <-70° C., and stirring was continued for an additional 1 h. The solution was allowed to warm to 0° C., quenched with 2 N HCl and extracted with methylene chloride. The organic solution was washed with brine, dried and concentrated to give 3.6 g of 2-(trimethylsilyl-3-benzofurancarboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH:5]([C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24](=[O:40])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:18][CH:17]=1)[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])C.O[Li].O>CO.O>[C:36]([O:35][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:24](/[CH:23]=[CH:22]/[C:19]1[CH:18]=[CH:17][C:16]([CH:5]([CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:4]([OH:41])=[O:3])=[CH:21][CH:20]=1)=[O:40])=[O:34])([CH3:38])([CH3:37])[CH3:39]
Reactant: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCO[Si](C)(C)C(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.8 %

Procedure:
To a solution of (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid ethyl ester (2.63 g, 4.52 mmol) in MeOH/H2O (30 mL/10 mL) was added LiOH.H2O (556 mg, 13.56 mmol). This mixture was stirred for about 5 h at room temperature, and then evaporated to remove most of the MeOH. The aqueous layer was acidified with concentrated HCl to pH 5-6. The acidified aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain 2.0 g (80%) of a yellow solid product. MS: calc'd 555 (MH+), exp 555 (MH+).
Reaction SMILES: [BH4-].[Na+].C(Cl)Cl.CO.[CH:8]([C:10]1[CH:14]=[C:13]2[C:15]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=3[NH:79][C:80](=[O:85])[C:81]([CH3:84])([CH3:83])[CH3:82])=[C:16]3[N:20]=[C:19]([C:21]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=4[NH:66][C:67](=[O:72])[C:68]([CH3:71])([CH3:70])[CH3:69])=[C:22]4[NH:26][C:25](=[C:27]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=5[NH:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C:28]5[CH:29]=[CH:30][C:31](=[C:33]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=6[NH:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C:11]=1[NH:12]2)[N:32]=5)[CH:24]=[CH:23]4)[CH:18]=[CH:17]3)=[O:9]>O>[OH:9][CH2:8][C:10]1[CH:14]=[C:13]2[C:15]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=3[NH:79][C:80](=[O:85])[C:81]([CH3:84])([CH3:83])[CH3:82])=[C:16]3[N:20]=[C:19]([C:21]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=4[NH:66][C:67](=[O:72])[C:68]([CH3:69])([CH3:70])[CH3:71])=[C:22]4[NH:26][C:25](=[C:27]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=5[NH:53][C:54](=[O:59])[C:55]([CH3:56])([CH3:57])[CH3:58])[C:28]5[CH:29]=[CH:30][C:31](=[C:33]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=6[NH:40][C:41](=[O:46])[C:42]([CH3:43])([CH3:44])[CH3:45])[C:11]=1[NH:12]2)[N:32]=5)[CH:24]=[CH:23]4)[CH:18]=[CH:17]3
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1c2nc(c(-c3ccccc3NC(=O)C(C)(C)C)c3cc(C=O)c([nH]3)c(-c3ccccc3NC(=O)C(C)(C)C)c3nc(c(-c4ccccc4NC(=O)C(C)(C)C)c4ccc1[nH]4)C=C3)C=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)Nc1ccccc1-c1c2nc(c(-c3ccccc3NC(=O)C(C)(C)C)c3cc(CO)c([nH]3)c(-c3ccccc3NC(=O)C(C)(C)C)c3nc(c(-c4ccccc4NC(=O)C(C)(C)C)c4ccc1[nH]4)C=C3)C=C2
Reaction time: 0.25 h

Procedure:
NaBH4 (41.5 mg, 1.1 mmol) was added to a solution of CH2Cl2 --MeOH (1/3 v/v) (8 ml) containing 2-formyl-5,10,15,20-tetrakis(o-pivalamidophenyl)porphyrin (0.11 g, 0.11 mmol) under argon stirred for 15 min. After adding water to the solution, the mixture was extracted by CHCl3 and washed with water. After drying (Na2SO4), the organic layer was chromatographed on a silica gel flash column using CHCl3 --MeOH (10/1 v/v) as the eluent. The residue was dried at room temperature in vacuo to give a purple product, (2-hydroxymethyl-5,10,15,20-tetrakis(o-pivalamidophenyl)porphyrin, 0.11 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[O-]CC.[Na+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1cccc(O)c1C
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(OCCCC(=O)O)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,3-Dimethylphenol (24.5 g, 0.2 mol) was dissolved in 125 ml of anhydrous ethanol. Seventy five (75) ml of 21 wt % sodium ethoxide solution in ethanol (0.2 mol) was added to the solution. The mixture solution was stirred at room temperature for 10 min. Ethyl 4-bromobutyrate (40 g, 0.205 mol) was then added to the solution. The reaction mixture was refluxed at 80° C. for 24 h. The precipitate was filtered of. The filtrate was then mixed with a solution of sodium hydroxide (10 g, 0.25 mol) in 150 ml of water. The mixture was stirred at 70° C. for about 2 hours, and monitored with HPLC. The mixture was diluted with 150 ml of water and acidified to pH 1. Oily precipitate formed immediately. The precipitate was collected by decanting the supernatant and washed with water twice (100 ml×2). The oily precipitate solidified after being kept in water at room temperature overnight.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15]OS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:4]1[CH:3]=[CH:2][C:1]([C@H:7]2[O:15][C@@H:8]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Reactant: O=S([O-])OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Yield: 85 %

Procedure:
Reaction at 20° C.: trans-Stilbene (0.181 g, 1 mmol) was dissolved in acetonitrile/DMM (15 mL, ½, V/V). subsequently were added buffer (10 mL, 0.05 M solution of Na2B4O7.H2O in 4×10−4 M aqueous Na2EDTA), tetrabutylammonium hydrogen sulfate (0.015 g, 0.04 mmol), and ketone 1 (0.0774 g, 0.3 mmol). A solution of Oxone® (1.0 g, 1.6 mmol) in aqueous Na2EDTA (4×10−4 M, 6.5 mL) and a solution of K2CO3 (0.93 g, 6.74 mmol) in water (6.5 mL) were added dropwise separately over a period of 30 min (via additional funnels). The reaction was then worked up by the same procedure as Method A to afford trans-stilbene oxide (0.166 g, 85% yield, 97.9% ee).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:31])[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:17]=[C:18]2Cl)=[CH:13][C:12]=1[O:29][CH3:30])=[O:10]>>[CH3:31][N:8]([CH3:7])[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:17]=[C:18]2[O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][C:12]=1[O:29][CH3:30])=[O:10]
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1C(=O)N(C)C
Reactant: OC1CCCC1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC3CCCC3)c2cc1C(=O)N(C)C

Procedure:
Similar procedure as described in example 400 was used, starting from cyclopentanol and of 1-Chloro-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid dimethylamide to give 1-Cyclopentyloxy-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid dimethylamide, LC-MS: m/e 410(MH+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][CH:7]1[C:11](=C)[CH2:10][CH2:9][C:8]1([CH:16]([CH3:18])[CH3:17])[C:13]([NH2:15])=[O:14].[O:28]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:24][C:22]([F:23])([F:25])[C:20]1[CH:19]=[C:5]([CH:4]=[C:3]([C:2]([F:26])([F:27])[F:1])[CH:21]=1)[CH2:6][CH:7]1[C:11](=[O:28])[CH2:10][CH2:9][C:8]1([CH:16]([CH3:18])[CH3:17])[C:13]([NH2:15])=[O:14]
Reactant: O=[O+][O-]
Reactant: C=C1CCC(C(N)=O)(C(C)C)C1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)C1(C(N)=O)CCC(=O)C1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzyl 3-methylene-1-isopropylcyclopentane-carboxamide (910 mg, 2.31 mmol) in dichloromethane (50 mL) was cooled to −78° C. and a stream of ozone was passed through until the permanent blue color indicated complete consumption of the olefin. The excess ozone was purged with a stream of nitrogen, and triphenylphosphine (729 mg, 2.78 mmol) was added. The cooling bath was removed, and the reaction mixture was allowed to stir at ambient temperature overnight. The solvent was removed in vacuo, the residue was purified by column chromatography (silica gel, ethyl acetate:hexane/1:2) to give 760.7 mg (83%) of the desired product. 1H NMR (500 MHz, CDCl3): 7.81 (s, 1H), 7.74 (s, 2H), 6.16 (bs, 1H), 6.61 (m, 2H), 2.78 (bd, J=18.07 Hz, 1H), 2.40 to 2.20 (bm, 4H), 2.08-1.98 (m, 2H), 0.99 (d, J=6.86 Hz, 3H), 0.97 (d, J=6.87 Hz, 3H).
Reaction SMILES: [Na].[C:2]([C:4]([C:11]#[N:12])=[C:5]([NH:8][C:9]#[N:10])[S:6][CH3:7])#[N:3].[BrH:13]>C(O)(=O)C>[NH2:10][C:9]1[N:3]=[C:2]([Br:13])[C:4]([C:11]#[N:12])=[C:5]([S:6][CH3:7])[N:8]=1
Reactant: Br
Reactant: CSC(NC#N)=C(C#N)C#N
Agent: [Na]
Solvent: CC(=O)O
Product: CSc1nc(N)nc(Br)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred suspension of 1.00 g (5.37 mmol) 2,2-dicyano-1-methylsulfanyl-vinyl-cyanamide sodium salt in 10 ml acetic acid at 5° C. was added dropwise 10 ml hydrobromic acid solution (33% in acetic acid) and the mixture was stirred at room temperature for 30 minutes. The mixture was then poured onto 100 ml ice-water added. The resulting crystals were collected by filtration and washed with water (ca 500 ml) until the washings were free of bromide ion. Chromatography (ethyl acetate/hexane 1/4) afforded 1.09 g (83%) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 246 (M{81Br}+, 93), 244 (M{79Br}+, 94), 165 ([M—Br]+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:36].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:38]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:36][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: Cc1c(N(Cc2ccc(Oc3ccc(Br)c(O)c3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CO
Product: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Br

Procedure:
The product from Example 323B and ethyl glycolate were processed as described in Example 62A to provide the title compound. MS (ESI+) m/z 641 (M+H)+.
Reaction SMILES: CN(C=O)C.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([OH:20])[C:14]([CH2:21]/[CH:22]=[C:23](/[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])\[CH3:24])=[C:13]([OH:31])[CH:12]=1.[CH3:32][C@@H:33]([C@@H:42]1[C@@:46]2([CH3:63])[C@@H:47]([OH:62])[CH2:48][C@@H:49]3[C@@:54]4([CH3:60])[CH2:55][CH2:56][C@@H:57]([OH:59])[CH2:58][C@H:53]4[CH2:52][C@@H:51]([OH:61])[C@H:50]3[C@@H:45]2[CH2:44][CH2:43]1)[CH2:34][CH2:35][CH2:36][CH:37]([C:39]([OH:41])=[O:40])[CH3:38]>CS(C)=O.CC(O)C>[CH3:32][C@@H:33]([C@@H:42]1[C@@:46]2([CH3:63])[C@@H:47]([OH:62])[CH2:48][C@@H:49]3[C@@:54]4([CH3:60])[CH2:55][CH2:56][C@@H:57]([OH:59])[CH2:58][C@H:53]4[CH2:52][C@@H:51]([OH:61])[C@H:50]3[C@@H:45]2[CH2:44][CH2:43]1)[CH2:34][CH2:35][CH2:36][CH:37]([C:39]([OH:41])=[O:40])[CH3:38].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O-:20])[C:14]2[CH:21]=[CH:22][C:23]([CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])([CH3:24])[O:31][C:13]=2[CH:12]=1
Reactant: CCCCCc1cc(O)c(C/C=C(\C)CCC=C(C)C)c(O)c1C(=O)O
Agent: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C)C(=O)O
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCCCCc1cc2c(c([O-])c1C(=O)O)C=CC(C)(CCC=C(C)C)O2

Procedure:
Table 6 below shows that DMSO, DMF, IPA and cyclodextrin facilitated solubilization of cannabinoids. Cyclodextrin solubilized up to 20-25 g/L of CBGA for conversion. Enzymatic rate was enhanced when 20% DMSO (v/v) was added to the reaction mixture and THCA synthase produced both THCA and CBCA in the reaction (Table 7).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([NH:13][CH2:14][CH:15]([C:17]2[CH:18]=[CH:19][C:20]([OH:27])=[C:21]([CH:26]=2)[C:22]([O:24]C)=O)O)[CH3:12])=[CH:5][CH:4]=1.C(=O)(O)[O-:29].[Na+]>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]([NH:13][CH2:14][C:15]2[C:21]([CH2:22][OH:24])=[C:20]([OH:27])[CH:19]=[CH:18][C:17]=2[CH2:26][OH:29])[CH3:12])=[CH:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc(C(O)CNC(C)CCc2ccc(F)cc2)ccc1O
Agent: Cl
Agent: [Na+]
Product: CC(CCc1ccc(F)cc1)NCc1c(CO)ccc(O)c1CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-[2-[[3-(4-Fluorophenyl)-1-methylpropyl]amino]-1-hydroxyethyl]-2-hydroxybenzoic acid, methyl ester, hydrochloride (2.66 g) was basified with 8% sodium bicarbonate solution (100 ml) and the free base was extracted into ether (3×100 ml). The dry extracts (MgSO4) were evaporated and the residual oil in tetrahydrofuran (40 ml) was added dropwise under nitrogen to a stirred solution of lithium aluminium hydride (0.74 g) in tetrahydrofuran (40 ml). When the addition was complete, the mixture was stirred at room temperature for 16 hours. The excess hydride was decomposed by the cautious addition of water (10 ml) and then the mixture was evaporated to dryness. The residue was diluted with 2 N hydrochloric acid (100 ml), basified with solid sodium bicarbonate and extracted with ether (2×50 ml). The combined extracts were dried (MgSO4) and diluted with light petroleum (b.p. 60°-80°) until turbid. The product precipitated as an off-white crystalline solid (1.21 g), m.p. 101°-103°. Recrystallization from ether-light petroleum (b.p. 60°-80°) gave colourless needles, m.p. 102°-103°.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([N:1]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 500 mg, 2.50 mmol) and potassium carbonate (518 mg, 3.74 mmol) in DMF (5 ml) was added (bromomethyl)benzene (CAS number 100-39-0; 356 μl, 3.00 mmol). The reaction was stirred at room temperature for 24 hours. To this was then added further (bromomethyl)benzene (CAS number 100-39-0; 356 μl, 3.00 mmol) and stirring was continued for 24 hours. The reaction mixture was diluted with ethyl acetate (40 ml) and washed with water (3×30 ml) and brine (30 ml). The organics were filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9]C)=O)=[O:4].[CH2:13]([CH2:15][NH2:16])[OH:14].C(N(CC)C(C)C)(C)C>O1CCCC1>[OH:14][CH2:13][CH2:15][N:16]1[CH2:2][C:3](=[O:4])[NH:5][C:6]([CH3:12])([CH3:11])[C:7]1=[O:9]
Reactant: COC(=O)C(C)(C)NC(=O)CCl
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)NC(=O)CN(CCO)C1=O
Temperature: 155 °C
Yield: 42.3 %

Procedure:
A solution of methyl 2-(2-chloroacetamido)-2-methylpropanoate (2.5 g, 13 mmol), ethanolamine (1.3 g, 21.3 mmol), and N,N-diisopropylethylamine (4.0 mL, 23 mmol) in 250 mL of anhydrous tetrahydrofuran was heated at reflux temperature for 24 hours. The mixture was concentrated to a residue in vacuo and dissolved in ethanol (approximately 300 mL). The mixture was heated in a sealed tube at 155° C. for 24 hours then concentrated to a crude residue and purified by column chromatography (5 to 12% methanol in dichloromethane) to give the title compound as a white solid (1.03 g, 5.5 mmol, 42%). 1H NMR (DMSO-d6, 400 MHz) δ 1.30 (s, 6H), 3.32-3.35 (t, J=5.7, 2H), 3.48-3.53 (q, J=5.7, 2H) 4.02 (s, 2H), 4.75-4.77 (t, J=5.4 Hz, 1H). LRMS (ESI/APCI) m/z 187 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([O:25]CC)=[O:24])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[N:11][C:10]=2[C:23]([OH:25])=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)O)c1
Yield: 101.1 %

Procedure:
Ethyl 5-(3-methoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (45.1 g) was dissolved in ethanol. 1 M Sodium hydroxide solution was added and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(3-methoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylic acid (42.1 g), melting point 116-118° C. (decomposition).
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][O:19][CH:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.C(O)(=O)C>C(O)(C)C>[C:1]1([C:7](=[N:18][O:19][CH:20]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON)C1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(ON=C(c2ccccc2)c2cc3ccncc3[nH]2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.2 %

Procedure:
To a mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (90 mg, 0.40 mmol) and tert-butyl 3-(aminooxy)pyrrolidine-1-carboxylate (Reference Example 9) (82 mg, 0.40 mmol) in isopropanol (6 mL) was added 4 Å molecular sieves. The pH of the solution was adjusted to pH 4-5 with glacial acetic acid. The reaction mixture was heated to reflux. After 3 days, the reaction mixture was cooled to ambient temperature. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. Purification by column chromatography (silica gel, 9.75:0.25 CH2Cl2/MeOH to 9.5:0.5 CH2Cl2/MeOH) followed by ion-exchange chromatography (SCX-2, 1:3 7 N NH4OH in MeOH/MeOH) gave tert-butyl 3-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]pyrrolidine-1-carboxylate (52.3 mg, 32%) as a mixture of isomers: mp 80-82° C.; 1H NMR (500 MHz, DMSO-d6) major isomer δ 1.37-1.39 (9H, m), 2.08-2.10 (2H, m), 3.13-3.17 (1H, m), 3.31-3.50 (3H, m), 4.92 (1H, br s), 6.23 (1H, s), 7.41-7.53 (6H, m), 8.08 (1H, d, J=5.4 Hz), 8.79 (1H, s), 11.85 (1H, s); ESI MS m/z 407 [C23H26N4O3+H]+; HPLC (Method A) 85.8% (AUC), tR=18.0 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C1(C)C=CC(S(O[CH2:30][CH2:31][Cl:32])(=O)=O)=CC=1>O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:30][CH2:31][Cl:32])=[CH:15][CH:14]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCOc1ccc(Br)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
The preparation was conducted according to the description in the document (J. Org. Chem., (2002), 67, 1093-1101). Potassium carbonate (83.0 g, 600 mmol) was added to an N,N-dimethylformamide (DMF, 500 mL) solution of 4-bromophenol (50.4 g, 291 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes, and then 2-chloroethyl p-toluenesulfonate (70.2 g, 299 mmol) was added thereto. The resulting mixture was stirred at 50° C. for 24 hours. The reaction solution was cooled to 110° C., and water (500 mL) was added thereto to precipitate a white solid. The solid was collected by filtration, washed with water (500 mL), and dried under reduced pressure to give 58.6 g of the title compound (white powder, yield: 86%).