Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[Br:2][C:3]1[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]([NH:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl:17][C:18]1[C:23]([C:24](Cl)=[O:25])=[C:22]([Cl:27])[C:21]([Cl:28])=[C:20]([Cl:29])[C:19]=1[Cl:30]>O1CCOCC1>[Cl:17][C:18]1[C:23]([C:24]([N:8]2[C:9](=[O:10])[C:4]3=[C:3]([Br:2])[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]3[C:6]2=[O:7])=[O:25])=[C:22]([Cl:27])[C:21]([Cl:28])=[C:20]([Cl:29])[C:19]=1[Cl:30]
Reactant: O=C(Cl)c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Agent: [K]
Solvent: C1COCCO1
Product: O=C(c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)N1C(=O)c2c(Br)c(Br)c(Br)c(Br)c2C1=O
Temperature: 25 °C

Procedure:
The potassium salt of 3,4,5,6-tetrabromophthalimide (0.10 mole) and dioxane (1200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentachlorobenzoyl chloride (0.10 mole) is then added dropwise, with stirring, to the reaction mixture at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is stripped of solvent to yield the desired product N-(pentachlorobenzoyl)-3,4,5,6-tetrabromophthalimide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([C:53]1[S:54][C:55]2[CH2:56][NH:57][CH2:58][CH2:59][C:60]=2[N:61]=1)=[O:52]>CN(C=O)C>[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([C:53]1[S:54][C:55]2[CH2:56][N:57]([C:12](=[O:14])[CH:11]=[CH:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:58][CH2:59][C:60]=2[N:61]=1)=[O:52]
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)C=Cc1ccc3c(c1)OCO3)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of 3-Benzo[1,3]dioxol-5-yl-acrylic acid (1.0 mmol) in dry 10 mL DMF, were added 1-hydroxybenzotriazole (1.2 mmol), 1 ethyl 3(3′ dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C. N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained from step VIII of example I was then added and mixture was stirred at room temperature overnight. Reaction mixture was concentrated, diluted with water, extracted with dichloromethane washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatography to get the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4](F)[CH:3]=1.O.[NH2:13][NH2:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8]([CH3:9])=[N:13][NH:14]2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(Br)cc1F
Reactant: NN
Solvent: O
Product: Cc1n[nH]c2cc(Br)ccc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
A suspension of 1-(4-bromo-2-fluorophenyl)ethanone (8.33 g, 38.4 mmol) in 15 mL of hydrazine monohydrate (309 mmol, 8 equiv) was heated to 120° C. under a reflux condenser for 23 hours. The resulting suspension (after cooling to room temperature) was filtered. The white solids were washed with water (2×15 mL), sucked under house vacuum at room temperature for 24 hours, and then dried under vacuum at room temperature over P2O5 for 24 hours to afford the title compound (7.59 g) as a yellow solid. LC-MS (ES) m/z=211, 213 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si](C)(C)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH2:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=O)[CH:26]=[CH2:27]>C1COCC1>[CH2:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[CH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:26]=[CH2:27]
Reactant: C=CCC1CCCCC1=O
Reactant: CC(C)(C)OC(=O)C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCC1CCCCC1=CC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
To a solution of diisopropylamine (6.60 mL, 46.6 mmol) in THF (200 mL) at −10° C., was added a solution 2.22M of n-butyllithium (20.4 mL, 44.4 mmol). The solution was stirred 15 min at −10° C., cooled down to −78° C. and tert-butyl 2-trimethylsilylacetate (9.7 mL, 44.4 mmol) in 1 mL of THF was added dropwise. The solution was stirred 15 min at −78° C., and 2-allylcyclohexanone (3.3 mL, 22.2 mmol) was added dropwise. The reaction mixture was stirred 1 h at −78° C. and 3 h at −25° C. It was then quenched with saturated NH4Cl, extracted with ethylacetate, washed with brine, dried and concentrated. Purification by flash chromatography (cyclohexane) gave tert-butyl 2-(2-allylcyclohexylidene)acetate (5.06 g, 96%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) 5.62 (1H, m), 5.41 (1H, s), 4.89 (2H, m), 3.83 (1H, m), 2.16 (3H, m), 1.90 (1H, m), 1.73 (1H, m), 1.61 (1H, m), 1.47-1.22 (4H, m), 1.36 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[NH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH2:34][CH2:33]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)NCCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
A solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (100 mg, 0.35 mmol, 1.0 equiv; Example 31, Step 1) in thionyl chloride (3.28 g, 2 ml, 27.6 mmol, 230 equiv; [CAS RN 7719-09-7]) was heated to 100° C. for 1 h. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (452 mg, 595 μL, 3.5 mmol, 10.0 equiv; [CAS RN 7087-68-5]) and 1,2,3,4-tetrahydro-quinoxaline (56 mg, 0.42 mmol, 1.2 equiv; [CAS RN 3476-89-9]) and the reaction mixture was stirred at rt for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 17.3 mg (12%) of the title compound. MS (ISP): 400.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][OH:12].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:12][CH2:11][CH2:10][O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(C2OCCO2)c1
Yield: 96.8 %

Procedure:
3-Bromobenzaldehyde (4.00 g, 21.6 mmol), ethane-1,2-diol (6.03 mL, 108 mmol) and toluene-4-sulfonic acid monohydrate (186 mg, 1.08 mmol) were dissolved in toluene (80 mL), and the solution was stirred under reflux for 4 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (4.79 g, 20.9 mmol, 97%) was obtained as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Cl>O.C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(OCc2cccc(Cl)c2)cc1

Procedure:
The starting material is prepared as follows: To the stirring mixture of 244 g of p-hydroxybenzaldehyde, 360 g of potassium carbonate, 32 g of potassium iodide, 1.2 lt of 95% aqueous ethanol and 160 ml of water is added slowly 367 g of m-chlorobenzyl chloride. The mixture is stirred at reflux for four hours, cooled to 80° and 2 lt of warm water are added while stirring. The mixture is cooled, the precipitate collected, washed with water and recrystallized from methanol, to afford the 4-(3-chlorobenzyloxy)-benzaldehyde melting at 51°-54°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:15][C:14]3[C:17]([F:22])=[CH:18][CH:19]=[C:20]([F:21])[C:13]=3[F:12])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]nc(I)c2c1
Reactant: Fc1ccc(F)c(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnc2c(c1)c(I)nn2Cc1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.0 g (38.021 mmol) of the compound from Example 6A were initially charged in DMF (170 ml), and 9.41 g (41.823 mmol) of 2,3,6-trifluorobenzyl bromide and 13.62 g (41.82 mmol) of caesium carbonate were then added. The mixture was stirred at RT overnight. The reaction mixture was then added to water (200 ml) and stirred for 15 min A precipitate was filtered off with suction, washed with water and subsequently dried under high vacuum. This gave 12.1 g of the title compound (78% of theory).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:17])[NH:7][C:6]1=[O:18].C(N(CC)CC)C.Br[C:27]([C:53](=[O:62])[C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=1)([Cl:52])[C:28]([N:30]([C:37]([O:39][CH:40]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C(Cl)(Cl)Cl>[CH3:61][O:60][C:57]1[CH:56]=[CH:55][C:54]([C:53]([C:27]([N:7]2[C:6](=[O:18])[CH:5]([O:4][CH2:3][CH2:2][NH2:1])[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:8]2=[O:17])([Cl:52])[C:28]([N:30]([C:37]([O:39][CH:40]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])=[O:62])=[CH:59][CH:58]=1
Reactant: NCCOC1C(=O)NC(=O)N1Cc1ccccc1
Reactant: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Br)C(=O)c1ccc(OC)cc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(C(=O)c1ccc(OC)cc1)N1C(=O)C(OCCN)N(Cc2ccccc2)C1=O)c1ccccc1
Yield: 92.4 %

Procedure:
Into 100 ml of chloroform were dissolved 10 g of 5-(2-aminoethyloxy)-1-benzylhydantoin and 4 g of triethylamine. While stirring, a solution of 11.9 g of α-bromo-α-(4-methoxybenzoyl)-2-chloro-5-dodecyloxycarbonylacetanilide in 50 ml of chloroform was added dropwise over a period of about 1 hour at room temperature. After being stirred for an additional 2 hours, the reaction mixture was condensed under reduced pressure, and the residue was purified by the use of a chromatographic column to give 14.1 g of α-(4-methoxybenzoyl)-α-[5-(2-aminoethyloxy)-1-benzyl-3-hydantoinyl]-2-chloro-5-dodecyloxycarbonylacetanilide. Yield. 92%. Oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([N+:20]([O-:22])=[O:21])[CH:10]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:28][OH:29].C(N(CC)CC)C.C(=O)=O.CC#N>C(Cl)Cl.C(Cl)(Cl)Cl.CO.CCOC(C)=O.CN(C=O)C>[CH3:7][O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][OH:29])=[O:15])=[C:11]([N+:20]([O-:22])=[O:21])[CH:10]=1
Reactant: OC[C@@H]1CCCN1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxalyl chloride (9.22 g, 6.4 mL, 72.6 mmol, 1.1 eq) and DMF (cat) were added to a suspension of 4,5-dimethoxy-2-nitrobenzoic acid (1, 15.0 g, 66 mmol) in anhydrous CH2Cl2 (150 mL) under a N2 atmosphere. The suspension was stirred at room temperature for 18 hours. The resultant solution was added dropwise to a solution of (S)-(+)-2-pyrrolidine-methanol (7.33 g, 7.16 mL, 72.6 mmol, 1.1 eq) and triethylamine (14.77 g, 20.21 mL, 145 mmol, 2.2 eq) in anhydrous CH2Cl2 (100 mL) at −40° C. (dry ice/CH3CN) under a N2 atmosphere. The reaction mixture was allowed to come to room temperature and stirred for 18 h. The mixture was washed with 1 M HCl (3×200 mL), H2O (2×200 mL), satd NaCl(aq) (200 mL), dried (MgSO4) and evaporated in vacuo to give a yellow foam. Trituration with 3% MeOH/EtOAc gave a white solid. Filtration and concentration of the filtrate gave a second crop of white solid. Total yield (18.13 g, 88.5%). mp 124.4-127.8° C.; [α]25D−109.00 (c=1.0, CHCl3); 1H NMR (CDCl3) δ 7.71 (s, 1H), 6.61 (s, 1H), 4.44-4.39 (m, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.98-3.76 (m, 2H), 3.18 (m, 2H), 2.23-2.13 (m, 3H), 1.92-1.69 (m, 1H); 13C NMR (CDCl3) δ 164.4, 154.5, 149.2, 137.1, 127.8, 109.0, 107.2, 65.7, 61.3, 56.8, 56.5, 49.5, 28.3, 24.3; IR (neat) 3343, 2940, 1605, 1530, 1337, 1276, 1109, 1064, 992, 862, 788, 756 cm−1; HRMS m/z calcd for C14H18N2O7 310.1234 (M+H) found 311.1243.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[C:11]([O:19]C)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([O:9][C:11](=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:6]([CH3:8])[CH3:7])(=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C(O)C(C)(C)CO
Reactant: COC(=O)c1ccccc1
Product: CC(C)C(OC(=O)c1ccccc1)C(C)(C)COC(=O)c1ccccc1

Procedure:
A process according to claim 1 wherein 2,2,4-trimethyl-1,3-pentanediol is transesterified with methyl benzoate to produce 2,2,4-trimethyl-1,3-pentanediol dibenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.Cl[C:11]([O:13][CH3:14])=[O:12]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:12])[O:13][CH3:14])=[C:4]([I:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Nc1ccc(Br)cc1I
Temperature: 25 °C
Yield: 97.7 %

Procedure:
To solution of 4-bromo-2-iodoaniline (18.50 g, 62.08 mmol) in pyridine (120 mL) at −10° C. was added methyl chloroformate (7.50 mL, 97.46 mmol) over 30 min via syringe pump. Reaction was allowed to warm to room temperature and was diluted with H2O (450 mL). Solid which was formed was collected by filtration, washed with H2O and dried in dessicator. Methyl 4-bromo-2-iodophenylcarbamate (21.59 g, 98%) was obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:35][CH2:34]1>CN(C=O)C.C(OCC)(=O)C>[CH:33]1([CH2:32][O:1][C:2]2[CH:24]=[CH:23][C:5]3[N:6]=[C:7]([N:9]4[CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:13][CH2:14]4)[O:8][C:4]=3[CH:3]=2)[CH2:35][CH2:34]1
Reactant: CC(=O)NC(C)CCC1CCN(c2nc3ccc(O)cc3o2)CC1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)CCC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To a solution of N-{3-[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]-1-methylpropyl}acetamide (0.49 g) in DMF (15 mL) were added potassium carbonate (0.41 g) and (bromomethyl)cyclopropane (0.41 g), and the mixture was stirred at 100° C. for 6 hr. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate/methanol to give the title compound (313 mg).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]4[S:32][C:31]([CH3:33])=[C:30]5[C:26]=4[CH2:27][C@H:28]4[C:34]([CH3:36])([CH3:35])[C@H:29]45)[O:22][N:21]=3)=[CH:15][C:14]=2[CH3:37])([N+:8]([O-:10])=[O:9])[CH2:4][O:3]1.[OH-].[Na+]>C1COCC1.C(O)(C(F)(F)F)=O.O.C(O)(C(F)(F)F)=O.O>[CH3:19][C:18]1[CH:17]=[C:16]([C:20]2[N:24]=[C:23]([C:25]3[S:32][C:31]([CH3:33])=[C:30]4[C:26]=3[CH2:27][C@H:28]3[C:34]([CH3:35])([CH3:36])[C@H:29]34)[O:22][N:21]=2)[CH:15]=[C:14]([CH3:37])[C:13]=1[O:12][CH2:11][C:5]([N+:8]([O-:10])=[O:9])([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCC1([N+](=O)[O-])COC(C)(C)OC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCC(CO)(CO)[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 98.8 %

Procedure:
A suspension of 3-[4-(2,2-dimethyl-5-nitro-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-phenyl]-5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazole (85 mg, 0.158 mmol) in THF:TFA:water 20:4:1 (12.5 mL) is stirred at 65° C. for 4.5 h. The mixture is further diluted with TFA:water 2:1 (1.5 mL) and stirring is continued at 65° C. for 3 h. The mixture is cooled to rt, poured onto 2N aq. NaOH and extracted twice with DCM. The organic extracts are dried over MgSO4 and evaporated to give 2-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxymethyl}-2-nitro-propane-1,3-diol (78 mg) as a beige resin; LC-MS: tR=1.17 min, [M+1]+=500.89.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[OH-].[Na+].Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>O.CO>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: OCCCCCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(=O)c2c(ncn2CCCCCCCO)n(C)c1=O
Temperature: 70 °C
Yield: 21.4 %

Procedure:
18 g of theophylline are added under stirring at room temperature to a solution of 4.1 g of sodium hydroxide in 50 ml of water and 50 ml of methanol. After stirring the mixture at 70° C. 15.8 g of 7-chloro-1-heptanol are added. The mixture is then maintained at 70° C. for 22 hours and then it is subjected to evaporation under reduced pressure until it is dry. The residue is dissolved in 150 ml of 1-N-sodium hydroxide and the mixture is extracted with methylene chloride. After washing out with water and drying over sodium sulfate the methylene chloride solution is concentrated under reduced pressure and the oily residue is several times recrystallized from diisopropyl ether. 6.3 g of 1,3-dimethyl-7-(7'-hydroxyheptyl)-xanthine are obtained (yield, referred to reacted theophylline, =79.3%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][C:11]=1[CH2:10][CH2:9]3.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)(=O)C>[C:27]([O:20][C:13]1[CH:14]=[CH:15][C:16]2[C@@H:17]3[C@H:8]([C@H:5]4[C@@:3]([CH2:19][CH2:18]3)([CH3:4])[C:2](=[CH2:1])[CH2:7][CH2:6]4)[CH2:9][CH2:10][C:11]=2[CH:12]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(OC(C)=O)ccc4[C@H]3CC[C@]12C

Procedure:
A solution of 17-methylenestra-1,3,5(10)-trien-3-ol (10, 5.84 g, 21.8 mmol) in anh. pyridine (32 mL, 0.40 mol) and acetic anhydride (9.7 mL, 0.10 mol) was stirred 24, after which ethyl acetate (250 mL) was added. See FIG. 17. The mixture was washed with three 100 mL portions of 1N hydrochloric acid+100 mL of saturated sodium bicarbonate+100 mL of saturated copper sulfate+100 mL of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 mL of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol gave lustrous white platelets (5.84 g, 18.8 mmol), m.p. 77°-79° C. (NA-1994A-248B)
Reaction SMILES: NC1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[O:10])[CH2:4]C1.C(OC([N:24]1CC[C@@H](N)C1)=O)(C)(C)C>>[NH:24]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[O:10])[CH2:4]1
Reactant: NC1CCC(NC(=O)N2CC[C@@H](N)C2)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: N[C@@H]1CCN(C(=O)N[C@@H]2CCNC2)C1

Procedure:
(R)-3-Amino-pyrrolidine-1-carboxylic acid (R)-pyrrolidin-3-ylamide is prepared analogously to (R)-3-amino-pyrrolidine-1-carboxylic acid (4-amino-cyclohexyl)-amide (Intermediate IF) by replacing (4-amino-cyclohexyl)-carbamic acid tert-butyl ester with (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:7](/[CH:10]=[CH:11]/[C:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([O:15]CC)=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:7](/[CH:10]=[CH:11]/[C:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:13]([OH:15])=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C/C(Cc2ccccc2)(Cc2ccccc2)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ncc(/C=C/C(Cc2ccccc2)(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Yield: 65.4 %

Procedure:
A solution of ethyl (E)-4-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2,2-bis(benzyl)-3-butenoate (121 mg) in ethanol (5 mL) was heated to reflux with 10% sodium hydroxide solution (3 mL) for 2 hours. The ethanol was evaporated, water was added and the aqueous layer was extracted with ether. The water layer was acidified to pH 1 with dilute hydrochloric acid solution, extracted with ethyl acetate, dried and concentrated to a solid. Trituration with ether provided 75 mg of the white solid hydrochloride salt of the title compound; mp 184°-185° C.