Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.Cl.[C:19]1(=[O:29])[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([N:7]2[C:3]([CH2:2][N:26]3[CH2:27][CH2:28][C:23]4([C:19](=[O:29])[NH:20][CH2:21][CH2:22]4)[CH2:24][CH2:25]3)=[N:4][N:5]=[N:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1NCCC12CCNCC2
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1NCCC12CCN(Cc1nnnn1-c1cccc(C(F)(F)F)c1)CC2
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (200 mg, 0.762 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (4 mL) was added 2,8-diazaspiro[4.5]decan-1-one hydrochloride (290 mg, 1.52 mmol, Tyger Scientific, Ewing, USA) and triethylamine (0.318 mL, 2.29 mmol). The reaction mixture was heated at 120° C. for 20 minutes in a microwave reactor. The reaction mixture was then cooled and the solvent removed under vacuum. The residue was purified by MDAP. Fractions containing the desired product were combined and the solvent removed. The product was partitioned between DCM (6 mL) and saturated aqueous NaHCO3 (3 mL) and the organic layer collected via a hydrophobic frit. The solvent was removed under a stream of argon to yield the title compound as a solid (0.161 g).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[Cl:25])=[CH:22][CH:21]=[CH:20][CH:19]=2>ClCCl>[Cl:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH:14][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Butyryl chloride (3.77 mL, 1.3 eq) and triethylamine (5.85 mL, 1.3 eq) were added sequentially to a chilled (0° C.) solution of 3-amino-4-chloroquinoline (5.0 g, 1.0 eq) in dichloromethane (100 mL). The reaction mixture was warmed to ambient temperature and then allowed to stir overnight. The reaction mixture was quenched with aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 6.5 g of N-(4-chloroquinolin-3-yl)butyramide.
Reaction SMILES: [H-].[Na+].C([C:10]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=1[OH:12])C1C=CC=CC=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(COC)OC>[CH2:19]([O:12][C:11]1[CH:10]=[CH:16][C:15]([OH:17])=[CH:14][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCBr
Reactant: Oc1ccc(O)c(Cc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCOc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
Sodium hydride (2.4 g, 0.1 mol) was suspended in 150 mL dry glyme. Monobenzylhydroquinone (20.0 g, 0.1 mol) was dissolved in 250 mL dry glyme and added dropwise to the sodium hydride suspension with stirring under nitrogen at room temperature. 1-Bromohexane (16.5 g, 0.1 mol) was added dropwise and the reaction mixture was refluxed for 1 day. The reaction product was cooled and the glyme removed under reduced pressure. The residue was dissolved in 300 mL 1:1 ethanol-ethyl acetate and catalytically hydrogenated using 2 g 10% Pd on C and a hydrogen pressure of 500 kPa at room temperature for 4 hours. The catalyst was removed by filtration and the solvent was removed from the filtrate under reduced pressure. The crude product residue was recrystallized from aqueous ethanol to yield 15 g 4-hexyloxyphenol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][NH:8][C:7]2=[O:13])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[C:20](#[N:23])[CH:21]=[CH2:22]>O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][CH2:21][C:20]#[N:23])[NH:8][C:7]2=[O:13])([O-:3])=[O:2]
Reactant: C=CC#N
Reactant: O=c1[nH][nH]c2ccc([N+](=O)[O-])cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#CCCn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
5-Nitro-1,2-dihydro-indazol-3-one (prepared according to Org. Synth. 1949, 29, 54 or Chem Ber. 1942, 75, 1104) (0.6 g) was suspended in water (8 mL) and 2N K2CO3 (aq.) (1.8 g) was added to the flask and the mixture was heated to 50° C. for 10 minutes. Acrylonitrile (0.24 mL) was then added dropwise. The reaction was stirred overnight and was quenched with 2 N HCl (aq.) solution while cooling in an ice bath. The aqueous phase was extracted with EtOAc and the combined phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo. Flash column chromatography over silica gel (eluting with EtOAc, nheptane, 3% AcOH) afforded pure desired 3-(5-Nitro-3-oxo-2,3-dihydro-indazol-1-yl)-propionitrile as a white solid. MS (ESI+: 233.3[M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1.O.[NH2:16][NH2:17]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:16][NH2:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1
Reactant: Clc1cc(N2CC=CCC2)c(Cl)nn1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc(N2CC=CCC2)c(Cl)nn1
Yield: 88 %

Procedure:
A mixture of 3,6-dichloro-4-(3,6-dihydro-2H-pyridin-1-yl)pyridazine (1.7 g, 7.4 mmol) and hydrazine hydrate (2.2 ml) in dioxan was stirred and heated at reflux under nitrogen for 24 hours. Upon cooling the dioxan was removed in vacuo and the residue was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane (×3). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was triturated with ether/MeOH and dried in vacuo to afford the title pyridazine (1.5 g, 88%). 1H NMR (250 MHz, d6-DMSO) 7.8 (1H, br s), 6.48 (1H, s), 5.76 (2H, m), 4.21 (2H, br s), 3.51 (2H, m), 3.24 (2H, m), 2.16 (2H, m). MS (ES+) 226 [MH]+, 228 [MH]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N-:15]=[N+]=[N-].[Na+].OS(O)(=O)=O.N#N>CC(O)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:14])[NH:15][C:12]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: [N-]=[N+]=[N-]
Agent: N#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCCc2ccc([N+](=O)[O-])cc2N1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
7.87 g of 7-nitro-1-tetralone from step A were placed in 55 ml of AcOH. Next, 7.0 g of NaN3 were added and the resulting mixture was heated to 60° C. Then, 10.3 ml of conc. H2SO4 were slowly added dropwise. N2 evolution took place and the temperature rose to 90° C. The reaction mixture was held at this temperature for 1/2 hour, then cooled and poured cautiously into an ice/28% NaOH solution. The mixture was extracted thoroughly with AcOEt, washed with a small amount of water, dried and evaporated. Flash chromatography on SiO2 (hexane/ethyl acetate (1/1→pure ethyl acetate)) yielded 2.58 g of 2,3,4,5-tetrahydro-8-nitro-2-oxo-1H-1-benzazepine as brown crystals of m.p. 224°-226° C. besides regioisomeric lactam and unreacted starting material.
Reaction SMILES: [H-].[Na+].[CH:3](=[N:10][N:11]=[C:12]1[NH:16][C:15](=[O:17])[CH2:14][N:13]1[CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O.C(Cl)(Cl)Cl.O>[CH:3](=[N:10][N:11]=[C:12]1[N:16]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:15](=[O:17])[CH2:14][N:13]1[CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCl
Reactant: COC(=O)CN1CC(=O)NC1=NN=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)CN(CC(=O)OC)C1=NN=Cc1ccccc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
In 20 ml of dimethylformamide (DMF) was suspended 96 mg of 60% sodium hydride under ice-cooling, 5 ml of a DMF solution of 548 mg of 2-benzylidenehydrazono-1-methoxycarbonylmethylimidazolidin-4-one was gradually added to the suspension. After stirring the mixture for one hour at 30° C., 254 mg of ethyl chloroacetate was gradually added dropwise thereto, followed by stirring for one hour at 80° C. After cooling the reaction mixture, water and chloroform was added thereto to distribute the mixture between water and chloroform, and the aqueous layer was further extracted three times with chloroform. The organic layer was combined with the extract, the mixture was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue formed was recrystallized from a mixture of chloroform and n-hexane to obtain 320 mg of 2-benzylidenehydrazono-3-ethoxycarbonylmethyl-1-methoxycarbonylmethylimidazolidin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[C:10]=1[C:11]([O:13]CC)=[O:12]>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1c(F)ccc2nn[nH]c12
Agent: Cl
Product: O=C(O)c1c(F)ccc2nn[nH]c12
Yield: 90.1 %

Procedure:
ethyl 6-fluoro-1H-1,2,3-benzotriazole-7-carboxylate (920 mg) was heated in 6N HCl until all of the starting material disappeared. Evaporation of the HCl afforded 718 mg of a brownish solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]3[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:9]2=3)[CH2:4][CH2:3]1.[CH2:26]([NH:28]CC)[CH3:27]>>[CH2:26]([NH:28][C:23]([C:20]1[CH:21]=[CH:22][C:9]2[C:8](=[C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]=2[CH:19]=1)=[O:24])[CH3:27]
Reactant: CN1CCC(=C2c3ccccc3COc3cc(C(=O)O)ccc32)CC1
Reactant: CCNCC
Product: CCNC(=O)c1ccc2c(c1)OCc1ccccc1C2=C1CCN(C)CC1

Procedure:
The title compound was synthesized from compound 4d using an adaptation of Procedure 6, substituting ethylamine for diethylamine. MS m/z (MH+) 363.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Clc1cccc(C2CNc3ccccc32)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(c2cccc(Cl)c2)c2ccccc21
Reaction time: 1.5 h

Procedure:
To a solution of 3-(3-chlorophenyl)indoline (3.88 g, 16.9 mmol) and DIEA (2.40 g, 18.6 mmol) in DCM (40 mL) was added dropwise methanesulfonyl chloride (2.13 g, 18.6 mmol) at about 0° C. The mixture was stirred for about 1.5 hours. The solution was diluted with DCM and washed with saturated NaHCO3 solution (2 times), 1N HCl aqueous solution (2 times) and brine (2 times) and dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with EtOAc/hexane 1:4. The title compound was obtained as an oil Yield: 4.40 9, 85%. Rf=0.41, silica, EtOAc/hexane 1:2. 1H NMR (300 MHz, CDCl3) δ:7.52 (d, 1H), 7.24-7.34 (m, 3H), 7.20 (s, 1H), 7.02-7.14 (m, 3H), 4.59 (t, 1H), 4.38 (t, 1H), 3.87 (dd, 1H), 2.92 (s, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:9]([OH:13])[C@H:10]([OH:12])[CH3:11].N1C=CN=C1>ClCCl>[O:13]([CH2:9][C@H:10]([OH:12])[CH3:11])[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](O)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Yield: 96 %

Procedure:
A solution of tert-butyldimethylchlorosilane (9.9 g, 65.7 mmol) in dichloromethane was added dropwise to a solution of (R)-(−)-1,2-propanediol (5 g, 65.7 mmol) and imidazole (4.47 g, 65.7 mmol) in anhydrous dichloromethane at 0° C. The reaction mixture was stirred at 0° C. for 30 min before dilution with dichloromethane. The solution was washed with water three times followed by the addition of brine. The organic layer was separated, dried through a MgSO4 pad and concentrated under reduced pressure to afford 12.0 g (96%) of (2R)-1-(tert-Butyldimethylsiloxy)propan-2-ol.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([Cl:29])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(C=O)cc1Cl
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1Cl

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-chloro-4-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 533.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[C:32](O)(=[O:35])[CH2:33][CH3:34]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:28][CH2:27]2)[N:10]=1
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 20 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and propionic acid (Aldrich), to give 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-propan-1-one. HRMS, observed: 384.2034; Calcd for (M+H)+: 384.2030.
Reaction SMILES: [F:1][C:2]([F:36])([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)[CH:3]([F:25])[O:4][C:5]([F:24])([F:23])[C:6]([F:22])([O:11][C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[C:7]([F:10])([F:9])[F:8].S(Cl)([Cl:39])=O>>[F:1][C:2]([F:36])([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([Cl:39])=[O:32])=[CH:29][CH:28]=1)[CH:3]([F:25])[O:4][C:5]([F:24])([F:23])[C:6]([F:22])([O:11][C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[C:7]([F:10])([F:9])[F:8]
Reactant: O=C(O)c1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1

Procedure:
4-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)benzoic acid (52.00 g, 0.0912 mol) as prepared in Example 12 and thionyl chloride (365 g, 3.09 mol) were place in an oven dried RB flask equipped with a stirrer, reflux condenser and under nitrogen. The reaction was placed in an oil bath and heated to a gentle reflux overnight. The content was analyzed by proton NMR and shown to be 4-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)benzoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[N:7]([CH3:14])[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:15])[N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10][CH2:9]1)[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=O
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of methylpiperidin-4-yl-carbamic acid tert-butyl ester (2.0 g, 9.4 mmol) in dichloromethane (50 mL) was added acetaldehyde (1.65 mL, 27.9 mmol). The resultant dark red solution was stirred for 10 minutes, then sodium triacetoxyborohydride (2.97 g, 14.0 mmol) was added portionwise. After 20 hours at ambient temperature, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution (100 mL) and dichloromethane (100 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (3×100 mL). The combined organic layer was (Na2SO4), filtered and concentrated in-vacuo. The resultant residue was purified by flash chromatography (silica, 70 g column, Si-SPE, ethyl acetate followed by 10% methanol in dichloromethane) to afford the title compound as an orange oil (1.64 g, 72%). 1H NMR (300 MHz, CDCl3): 3.01 (d, J=11.3 Hz, 2H), 2.74 (s, 3H), 2.41 (q, J=7.2 Hz, 2H), 1.98 (t, J=11.6 Hz, 2H), 1.76-1.72 (m, 5H), 1.46 (s, 9H), 1.08 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].I[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>[Cu](I)I.C(OCC)(=O)C>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[N:4]([C:1](=[O:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Ic1cccs1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N(c1ccccc1)c1cccs1
Temperature: 150 °C
Yield: 18.4 %

Procedure:
A mixture of acetanilide (6.0 g), 2-iodothiophene (18.6 g), copper iodide (864 mg), and potassium carbonate (12.2 g) was heated for 2 hours at 150° C. After the mixture was allowed to cool, water and ethyl acetate were added thereto. The resulting mixture was stirred, then filtered with celite. The aqueous phase was extracted. The organic phase was washed with water and saturated brine, and dried over sodium sulfate. The resulting solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:5) to obtain N-(2-thienyl)acetanilide (1.77 g; yield, 18%) as a light brown solid.
Reaction SMILES: [CH2:1]([OH:9])[CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:10][C:11]([CH3:13])=O>>[CH3:10][C:11]1([CH3:13])[O:8][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[CH2:1][O:9]1
Reactant: OCCCCC(O)CO
Reactant: CC(C)=O
Product: CC1(C)OCC(CCCCO)O1

Procedure:
15 g (112 mmol) of 1,2,6-hexanetriol were dissolved together with 0.5 g of FeCl3 in 1 l of acetone and boiled under reflux for 7 h. The mixture was filtered, and excess acetone was removed by distillation, resulting in the product in pure form.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35]C(=O)C)=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.CCCCCC>CO.ClCCl>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reaction time: 1 h

Procedure:
To a stirred suspension of (1S,2R,4aS,5R,8R,8aR)-2-(acetyloxy)-8a-hydroxy-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate, (Preparation 1, 1 g) in methanol (25 ml) was added a solution of concentrated hydrochloric acid (2 ml) in methanol (25 ml). After 5 days the reaction mixture was diluted with dichloromethane (150 ml), washed with water (3×100 ml), filtered through cotton wool and evaporated to dryness to give a yellow, oily solid. This residue was partially dissolved in dichloromethane (25 ml) and hexane (50 ml) was slowly added. After 1 hour, the suspension was filtered to give the product as an off-white solid (900 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:20]([O:27][C:28](=[O:38])[CH2:29][C:30]1([C:35](O)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[NH4+].[OH-]>CN(C=O)C.O.CCOC(C)=O>[CH2:20]([O:27][C:28](=[O:38])[CH2:29][C:30]1([C:35]([NH:1][CH2:2][CH:3]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:4]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5])=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CC1(C(=O)O)CCCC1)OCc1ccccc1
Reactant: COc1ccc(CC(CN)C(=O)OC(C)(C)C)cc1
Agent: On1nnc2cccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CC(CNC(=O)C2(CC(=O)OCc3ccccc3)CCCC2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
A solution of tert-butyl 3-amino-2-(4-methoxybenzyl)propanoate (50 mg, 0.188 mmol), 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid (49.4 mg, 0.188 mmol), EDC (47.0 mg, 0.245 mmol) and HOAt (33.3 mg, 0.245 mmol) in DMF (2 ml) was allowed to stir at room temperature for 3 hours. The reaction mixture was diluted with H2O and EtOAc. To the organic layer was added NH4OH (6 ml) and washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 50:50) to give tert-butyl 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-2-(4-methoxybenzyl)propanoate (56.3 mg); Retention time=1.61 minutes (condition B); MS (m+1)=510.5; 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 9H) 1.57-1.70 (m, 6H) 2.00-2.04 (m, 2H) 2.66-2.86 (m, 5H) 3.24-3.47 (m, 2H) 3.77 (s, 3H) 5.08 (s, 2H) 6.36-6.39 (m, 1H) 6.79-6.82 (m, 2H) 7.07-7.11 (m, 2H) 7.30-7.34 (m, 5H).
Reaction SMILES: [C:1]([NH:8][CH:9]([C:14]([O:16]CC1C=CC=CC=1)=[O:15])[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:1]([NH:8][CH:9]([C:14]([OH:16])=[O:15])[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(NC(=O)OC(C)(C)C)C(=O)O
Yield: 107 %

Procedure:
BOC-NHCH(CO2Me)CO2CH2Ph (16.2 g) was dissolved in MeOH (250 ml), to which was added 20% Pd/C (0.66 g). The suspension was purged with H2 for 1.5 hours, filtered, and stripped at 30° in vacuo, giving a syrup (12.5 g) which was kept at 4° until use in the following step.