Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[OH:25][CH:24]([C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])=[O:4]
Reactant: C#CC(=O)OCCOCCOC
Reactant: COc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCCOC(=O)C#CC(O)c1ccc(OC)cc1
Reaction time: 0.17 h

Procedure:
A solution of 10 g (58 mmol) of 2-(2-methoxyethoxy)-ethyl propiolate in 80 ml of tetrahydrofuran is treated at -78° under argon with 36 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 7 ml (58 mmol) of 4-methoxybenzaldehyde in 60 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 30 minutes, then brought to room temperature and treated with 150 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ether 4:1). There was obtained 2-(2-methoxyethoxy)ethyl 4-hydroxy-4-(4-methoxyphenyl)-2-butynoate as a red oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([CH3:9])([OH:8])[CH3:7])[CH:2]=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:18])C=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH3:7][C:6]([OH:8])([CH3:9])[CH2:5][O:4][CH2:1][CH:2]1[CH2:3][O:18]1
Reactant: C=CCOCC(C)(C)O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(O)COCC1CO1
Temperature: 0 °C
Reaction time: 6.5 h
Yield: 36.9 %

Procedure:
1-(Allyloxy)-2-methylpropan-2-ol (1.50 g, 11.5 mmol) was dissolved in DCM (50 mL) and cooled to 0° C. mCPBA (77%> max, 9.94 g) was added. The suspension was stirred at 0° C. for 6.5 hr. and then saturated NaHCO3 solution (˜20 ml) and Na2S2O3 solution (˜20 ml) were added. The resulting mixture was stirred at 0° C. for 15 min and the two layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 1:0 to 1:2) to give the product as a colorless oil (620 mg, 37%). 1H NMR (400 MHz, CDCl3) δ ppm 3.64 (1H, ddd, J= 12.0, 5.2, 2.8 Hz), 3.24-3.29 (1H, m), 3.17-3.21 (1H, m), 3.11-3.14 (1H, m), 2.97-3.00 (1H, m), 2.88 (1H, br s), 2.60-2.64 (1H, m), 2.44-2.47 (1H, m), 1.02 (6H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([N:20]([CH3:37])[NH:21][C:22](=[O:36])[CH2:23][CH2:24][NH:25][C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:38]([O:40][CH:41]([O:55][CH2:56][CH3:57])[CH2:42][NH:43][CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)[CH3:39].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>ClCCl.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([N:20]([CH3:37])[NH:21][C:22](=[O:36])[CH2:23][CH2:24][NH:25][C:26]([NH:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C:17]([N:43]([CH2:42][CH:41]([O:40][CH2:38][CH3:39])[O:55][CH2:56][CH3:57])[CH2:44][C:45]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH:48]=[CH:47][CH:46]=2)=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(NC(=O)CCNC(=O)NCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CCOC(CNCc1cccc2ccccc12)OCC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(C)NC(=O)CCNC(=O)NCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
To a solution of (S)-3-(4-(benzyloxy)phenyl)-2-(2-(3-(3-benzylureido)propanoyl)-1-methylhydrazinyl)propanoic acid (Compound VII-1) 126 mg (0.25 mmol) in dichloromethane 1.5 ml, 2,2-diethoxy-N-(naphthalen-1-ylmethyl)ethanamine (Compound IV-2) 85 mg (0.31 mmol) and DMT-MM 173 mg (0.63 mmol) were added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with chloroform 50 ml and washed with water 50 ml twice and brine 50 ml twice and dried over magnesium sulfate and filtered. The mother solution was concentrated in vacuo and the residue was purified on silica gel column chromatography (Merck 60N spherical, neutral 10 ml elution by chloroform:methanol=100:0 to 90:10, each elution 50 ml) to give the desired product as pale yellow oil 85.0 mg (35.8%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Br)ccc1OCc1ccccc1

Procedure:
A suspension of 2-benzyloxy-5-bromobenzaldehyde (14.5 g, 50.2 mmol) in absolute ethanol (250 ml) was treated with sodium borohydride (2.6 g, 68.8 mmol). The reaction was stirred and the temperature slowly rose to 33° C. After 1 hour the reaction mixture was evaporated and the residue dissolved in ethyl acetate and poured into a mixture of ice water (200 ml) and 1N HCl (25 ml). The organic layer was separated, washed with aqueous sodium hydrogen carbonate, brine, dried (Na2SO4) and evaporated to give 2-benzyloxy-5-bromobenzyl alcohol as a pale yellow oil (14.85 g, quantitative).
Reaction SMILES: C[C@]12CC[C@H]3[C@@H](C=CC4[C@]3(C)CCC(=O)C=4)[C@@H]1CCC2=O.CC(C)=O.[OH:26][C@H:27]1[C@@:43]2([CH3:44])[C@@H:39]([CH2:40][CH2:41][C:42]2=[O:45])[C@H:38]2[C@@H:29]([C@:30]3([CH3:47])[C:35]([CH2:36][CH2:37]2)=[CH:34][C:33](=[O:46])[CH2:32][CH2:31]3)[CH2:28]1>CCCCCC.C(OCC)(=O)C>[OH:26][C@H:27]1[C@@:43]2([CH3:44])[C@@H:39]([CH2:40][CH2:41][C:42]2=[O:45])[C@H:38]2[C@@H:29]([C@:30]3([CH3:47])[C:35]([CH:36]=[CH:37]2)=[CH:34][C:33](=[O:46])[CH2:32][CH2:31]3)[CH2:28]1
Reactant: C[C@@]12C(=O)CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1C[C@H]2O
Agent: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C[C@@]12C(=O)CC[C@H]1[C@@H]1C=CC3=CC(=O)CC[C@]3(C)[C@H]1C[C@H]2O

Procedure:
Product C is seen to contain compounds of low polarity. A portion (26 g) is chromatographed on silica gel using a gradient of acetone in chloroform to separate the components. From the eluate comprising 10% acetone a fraction containing IV is obtained. This is re-chromatographed on silica gel with equal parts of hexane and ethyl acetate as eluent and provides a fraction which on recrystallising the product from aqueous ethanol gives pure IV, seen to be androsta-4,6-diene-3,17-dione, melting point 171.5°-172.5° C. (0.65 g). Similarly an eluate comprising 15% acetone is seen to contain a mixture of products, V and VI. On re-chromatography as above with hexane-ethyl acetate the compound V elutes first and on recrystallising this product from aqueous ethanol gives pure V, shown to be 12β-hydroxyandrost-4-ene-3,17-dione, melting point 169°-70° C. (8.2 g). The product VI elutes soon after and on recrystallising the product from aqueous ethanol gives pure VI, 12β-hydroxyandrosta-4,6-diene-3,17-dione, melting point 195°-6° C. (0.75 g). Similarly, an eluate comprising 20-25% acetone is seen to contain a mixture of II and VII. On re-chromatography as before, component II elutes first and then VII. On recovering this latter component and re-crystallising from aqueous ethanol gives pure VII, seen to be 12α-hydroxyandrosta-1,4-diene-3,17-dione melting point 202°-3° C. (0.34 g). Similarly the eluate comprising 30-35% acetone is seen to contain III and VIII. On re-chromatography of this product with ethyl acetate-hexane the first component eluting is VIII. On recovering this product and recrystallising from aqueous ethanol pure VIII is obtained, shown to be 7α-hydroxyandrost-4-ene-3,17-dione melting point 248°-50° C. (0.22 g). Similarly the eluate comprising 35-40% acetone is seen to contain IX and X, eluting separately. The first product is recovered and on recrystallising from aqueous ethanol pure IX is obtained shown to be 12β,17β-dihydroxyandrost-4-ene-3,17-dione melting point 118°-19° C. (1.6 g). The second product is also recovered and on recrystallising from aqueous ethanol pure X is obtained, shown to be 12β,17β-dihydroxyandrosta-1,4-diene-3-one, melting point 174°-5° C. (0.79 g).
Reaction SMILES: [CH:1]([Si:4]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:9][CH2:8]1)([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[CH:21]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:18]([CH3:20])[CH3:19])[O:5][CH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:11][CH2:12]1)([CH3:22])[CH3:23]
Reactant: COC(=O)CC1CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[Si](OCC1CCC(CC(=O)O)CC1)(C(C)C)C(C)C

Procedure:
To a solution of 8.8 g (25.7 mmol) of methyl ester from Step E in 50 mL of THF and 50 mL of methanol was added 25 mL (24.9 mmol) of 1 N aqueous sodium hydroxide. The resultant mixture was stirred at room temperature overnight, and the solvent was removed under vacuum. The residue was diluted with ice water, and then acidified with 1 N aqueous hydrochloric acid. The mixture was extracted with three portions of ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and concentrated to provide a quantitative yield of the title compound. 1H NMR (500 MHz, CDCl3) δ 3.58 (d, 0.6H, J=6.7 Hz), 3.39 (d, 1.4H, J=6.2 Hz), 2.38 (d, 0.6H, J=4.4 Hz), 2.24 (d, 1.4H, J=3.9 Hz), 1.82–1.60 (m, 4H), 1.54 (m, 1H), 1.45 (m, 1H), 1.1–1.05 (m, 23H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:20]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:21]=[CH:22][N:23]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.CCCCC.[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[C:48](Cl)=[O:49]>C1COCC1>[C:27]1([S:24]([N:20]2[CH:21]=[C:22]([C:48]([C:47]3[CH:51]=[C:52]([O:56][CH3:57])[C:53]([O:54][CH3:55])=[C:45]([O:44][CH3:43])[CH:46]=3)=[O:49])[N:23]=[C:19]2[C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=2)(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=S(=O)(c1ccccc1)n1ccnc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)n2)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a solution of 1-(phenylsulfonyl)-3-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole (10ya) (5.0 mmol) in anhydrous THF (100 mL) at −78° C. was added 1.7 M tert-butyllithium in pentane (1.2 equiv, 6.0 mmol) and stirred for 10 min. A solution of 3,4,5-trimethoxybenzoyl chloride (1.2 equiv, 6.0 mmol) in THF was added at −78° C. and stirred overnight. The reaction mixture was quenched with 100 mL of saturated NaHCO3 solution (aqueous) and extracted by ethyl acetate (300 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 3:1) to give a white solid. Yield: 30%. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=10 Hz, 1H), 8.04 (d, J=10 Hz, 2H), 7.91 (s, 1H), 7.76 (d, J=5 Hz, 2H), 7.65 (t, J=10 Hz, 1H), 7.55-7.58 (m, 5H), 7.40 (s, 2H), 7.33-7.36 (m, 3H), 7.25 (t, J=10 Hz, 1H), 4.05 (s, 3H), 4.03 (s, 6H). MS (ESI) calcd for C33H27N3O8 657.0. found 680.1 [M+Na]+.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[CH2:20][O:21][CH2:22][O:23][CH3:24])CCC>C1(C)C=CC=CC=1>[CH3:20][O:21][CH2:22][O:23][CH2:24][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Reactant: COC(=O)c1ccc(Cl)n2ccnc12
Solvent: Cc1ccccc1
Product: COCOCc1ccc(C(=O)OC)c2nccn12
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a suspension of methyl 5-chloroimidazo[1,2-a]pyridine-8-carboxylate (1.115 g, 5.29 mmol) and tributyl({[(methyloxy)methyl]oxy}methyl)stannane (2.03 g, 5.56 mmol) in anhydrous toluene (10 mL) was added chloro(di-2-norbonylphosphino)(2′-dimethylamino-1,1′-biphenyl-2-yl)palladium (II) (300 mg, 0.535 mmol). The reaction vessel was sealed and heated in a Biotage Initiator microwave using initial absorption setting high to 170° C. for 1 hour. After cooling the reaction was poured onto a biphasic mixture of ethyl acetate (100 mL) and an aqueous potassium floride solution (2 g in 100 mL). The mixture was stirred rapidly and filtered through a pad of celite (10 g). The biphasic filtrate was separated and the aqueous layer back extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (100 g) using a 0-15% methanol-DCM gradient over 60 min. The appropriate fractions were combined and evaporated in vacuo to give impure material which was subjected to a second chromatographic purification on silica (100 g) using a 0-100% ethyl acetate-DCM gradient over 40 min followed by a 0-15% methanol-DCM gradient over 40 min. The appropriate fractions were combined and evaporated in vacuo to give still impure methyl 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carboxylate (302 mg, purity by LCMS/UV ca 65%) which was used directly in the next step.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:13][C:14](=[O:17])[O:15][CH3:16])[CH:11]=[CH2:12].C(N(CC)CC)C>C(OCC)C>[CH3:16][O:15][C:14]([NH:13][CH2:10][CH:11]1[O:9][N:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1)=[O:17]
Reactant: C=CCNC(=O)OC
Reactant: ON=Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)NCC1CC(c2ccccc2)=NO1
Temperature: 15 °C
Reaction time: 3 h

Procedure:
A 24 g. portion of benzaldoxime was chlorinated, isolated and dissolved in diethyl ether. The solution was cooled to 15° C., and 46 g. of methyl allylcarbamate was added. Sixty ml. of triethylamine was then added dropwise, keeping the temperature below 20° C. The mixture was stirred for 3 hours, and filtered. The filtrate was evaporated to dryness, and the residue was washed with water and filtered again. The solids were identified as 32 g. of product, m.p. 102°-103° C., NMR singlets at 3.63 and 5.48 ppm., multiplets at 2.82-3.80, 4.57-5.08, 7.13-7.50 and 7.45-7.77 ppm.
Reaction SMILES: [CH3:1][C@@:2]12[C@:10]3([C:16]([CH2:18][OH:19])=[O:17])[O:11][C:12]([CH3:15])([CH3:14])[O:13][C@@H:9]3[CH2:8][C@H:7]1[C@@H:6]1[CH2:20][CH2:21][C:22]3[C@@:28]([CH3:29])([C@@:5]1(F)[C@@H:4]([OH:31])[CH2:3]2)[CH:27]=[CH:26][C:24](=[O:25])[CH:23]=3.C[C@@]12[C@@](O)(C(CO)=O)[C@H](O)C[C@H]1[C@@H]1CCC3[C@@](C)([C@@]1([F:58])[C@@H](O)C2)C=CC(=O)C=3>>[CH3:29][C@@:28]12[C@H:5]3[C@@H:4]([OH:31])[CH2:3][C@:2]4([CH3:1])[C@:10]5([C:16]([CH2:18][OH:19])=[O:17])[O:11][C:12]([CH3:15])([CH3:14])[O:13][C@@H:9]5[CH2:8][C@H:7]4[C@@H:6]3[CH2:20][C@H:21]([F:58])[C:22]1=[CH:23][C:24](=[O:25])[CH2:26][CH2:27]2
Reactant: CC1(C)O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Product: CC1(C)O[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)CC[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1

Procedure:
Triamcinolone acetonide 0.1% (Kenalog®, Aristocort® A ointment)
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:24](Cl)(Cl)=[O:25].[NH2:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH2:1]([N:9]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:24](=[O:25])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][CH:39]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)CCC(C)(C)c2cc(NCCc3ccccc3)ccc21
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)N(CCc2ccccc2)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
A solution of phenethyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (9) (619 mg, 2.01 mmole) in 10 mL toluene was treated with 1.5 mL of a 20% phosgene solution in toluene and stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, the residue diluted with 15 mL of pyridine and then treated with 665 mg of ethyl p-aminobenzoate (2 eq.). The mixture was heated at 40° C. for 15 hours, then concentrated in vacuo to provide an orange oil. The product was purified by flash chromatography (SiO2, 15% ethyl acetate/hexanes, dry pack) to yield 441 mg (44%) of ethyl 4-[3-phenethyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (11) as a pale yellow foam.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(N(C)C)=O.[CH2:20]([N:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>O>[CH2:20]([N:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CCCCN(Cc1ccccc1)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCN(Cc1ccccc1)C(=O)N(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 3.89 g. of diphenylamine in 25 ml. of dimethylacetamide is added during one hour to a stirred mixture of 5.19 g. of N-benzyl-N-(n-butyl)carbamyl chloride, 0.685 g. of sodium hydride, and 65 ml. of dimethylacetamide under a nitrogen atmosphere at 45°-50° C. The mixture is stirred for 2 hours at 50° C. and then poured into water. The mixture is extracted with methylene chloride and the extract is evaporated. The residue is purified by chromatography using silica gel as the adsorbant and acetone-hexane as the eluent. After evaporation of the eluent, the residue is evaporatively distilled at 165° C. under reduced pressure (150 microns) to yield 1-benzyl-1-(n-butyl)-3,3-diphenylurea as a viscous, clear, clorless liquid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:9]1[C:21]([O:23]CC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.CCO.O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:9]1[C:21]([OH:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)c(C)cn1Cc1ccccc1
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(Cc2ccccc2)c(C(=O)O)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a suspension of ethyl 1-benzyl-3-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (8.50 g, 24.0 mmol) in THF (15 mL), EtOH (15 mL) and H2O (15 mL) was added LiOH.H2O (10.1 g, 240 mmol). The reaction mixture was stirred at reflux temperature for 2 h. To the reaction mixture were added extra H2O (45 mL) and EtOH (30 mL) and the reaction mixture was stirred at reflux temperature overnight. The reaction mixture was allowed to cool to room temperature and was almost completely concentrated. Aqueous 1 M KHSO4 (˜240 mL) was added to the reaction mixture while cooling with an ice-bath (pH reached 1), followed by the addition of EtOAc (500 mL). The organic layer was separated, washed with brine (2×400 mL), dried (Na2SO4) and concentrated. The residue was washed with a minimal amount of i-Pr2O and dried on a filter for 1 h to give ACI-02 (7.26 g, 93%).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[CH:5]([N:9]=[N:10][C:11](Cl)([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH2:7][CH3:8])[CH3:6].O>CC(C)=O>[CH:5]([N:9]=[N:10][C:11]([N:3]=[C:2]=[O:1])([CH2:13][CH:14]([CH3:15])[CH3:16])[CH3:12])([CH2:7][CH3:8])[CH3:6]
Reactant: CCC(C)N=NC(C)(Cl)CC(C)C
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCC(C)N=NC(C)(CC(C)C)N=C=O
Temperature: 25 °C

Procedure:
To a stirred solution of 8.6 grams (0.105 moles) of potassium cyanate in 75 ml of 70% aqueous acetone in a 125 ml erlenmeyer flask was added 19 grams (.093 moles) of 2-sec.-butylazo-2-chloro-4-methylpentane (from Example 3-23) over 10 minutes while holding the reaction temperature at 15°-20° C with a cold water bath. After the addition was complete the reaction was stirred an additional hour at room temperature, poured into 200 ml water and the product extracted with 100 mls of pentane. The pentane solution was separated, washed with 50 ml portions of water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 13.1 grams (67% crude yield). The infrared spectrum of the product was in agreement with the structure of 2-sec.-butylazo-2-isocyanato-4-methylpentane (strong broad isocyanate band at 2125-2225 cm- 1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH3:7])[CH3:2].C(O[CH:21](OCC)[N:22]([CH3:24])[CH3:23])C.CN(C=O)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=[CH:21][N:22]([CH3:24])[CH3:23])[CH3:2]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C(=O)OC
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)=C(C=CN(C)C)C(=O)OC
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of 2-ethoxycarbonyl-3-methoxycarbonyl-but-2-enoic acid ethyl ester (15 g, 61.5 mmol), dimethylformamide diethyl acetal (11.1 mL, 64.5 mmol) and DMF (15 mL) was heated at 80° C. for 5 h. After the mixture was cooled, 200 mL of benzene was added, and the resulting mixture was washed several times with 1 M HCl and water. The organic layer was dried over MgSO4 and concentrated to give an orange solid, which was recrystallized from hexanes/CCl4 to give 8.1 g of the title compound as a bright yellow solid. 1H NMR (CDCl3, 200 MHz): δ=6.70 (d, 1H, J=13.2 Hz), 5.66 (d, 1H, J=13.4 Hz), 4.10-4.40 (m, 4H), 3.88 (s, 3H), 2.96 (br s, 6H), 1.20-1.40 (m, 6H).