Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([CH3:12])[CH2:9][CH2:10]I)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH:21]2[CH2:24][NH:23][CH2:22]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([CH3:12])[CH2:9][CH2:10][N:23]1[CH2:24][CH:21]([O:20][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:26][CH:25]=2)[CH2:22]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(OC2CNC2)cc1
Reactant: C[C@H](CCI)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](CCN1CC(Oc2ccc(Cl)cc2)C1)NC(=O)OC(C)(C)C

Procedure:
A solution of ((R)-3-iodo-1-methyl-propyl)-carbamic acid tert-butyl ester (0.038 mg, 0.13 mmol), 3-(4-chloro-phenoxy)-azetidine hydrochloride (0.030 g, 0.13 mmol) and triethylamine (0.073 ml, 0.52 mmol) in DMF (1 ml) is stirred at room temperature for 18 hours. The reaction mixture is partitioned between ethylacetate and a saturated solution of sodium bicarbonate. The organic phase is washed with water and brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 1:1 ethylacetate:hexane as eluent to afford {(R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-carbamic acid tert-butyl ester. [M+H] 355.33
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:25]=[CH:24][C:13]3[C:14]4([CH3:23])[CH:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[C:6]([C:26]([F:29])([F:28])[F:27])[CH:5]=1)([O-:3])=[O:2].[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=4[C:26]([F:29])([F:27])[F:28])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: CC12CCC(=O)NC1CCc1cc(-c3ccc([N+](=O)[O-])cc3C(F)(F)F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc([N+](=O)[O-])cc4C(F)(F)F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-10bR)-8-(4-nitro-2-trifluoromethylphenyl)-10b-methyl-1,2,3,4, 4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (48 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide ! 0.022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 35 mg (70%) of the title compound as a white solid. mp 128°-130°. FDMS: m/e=418.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]([C:19]1[CH:20]=[C:21]([CH:25]2[C:29]3[C:30]([CH3:44])=[C:31]([NH:36][C:37](=[O:43])[CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:32]([CH3:35])=[C:33]([CH3:34])[C:28]=3[O:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1)=O.O>CN(C=O)C>[CH3:40][C:39]([CH3:42])([CH3:41])[CH2:38][C:37]([NH:36][C:31]1[C:32]([CH3:35])=[C:33]([CH3:34])[C:28]2[O:27][CH2:26][CH:25]([C:21]3[CH:20]=[C:19](/[CH:17]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:24]=[CH:23][CH:22]=3)[C:29]=2[C:30]=1[CH3:44])=[O:43]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1cccc(C=O)c1)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
To a solution of sodium hydride (a 60% dispersion in liquid paraffin, 79 mg, 1.98 mmol) in DMF (10 mL) was added dropwise at 0° C. under an argon atmosphere ethyl diethylphosphonoacetate (444 mg, 1.98 mmol) and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise at 0° C. a solution of N-(3-(3-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (684 mg, 1.80 mmol) obtained in Example 173 in DMF (5 mL) and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, was added to water and the product was extracted with ethyl acetate-THF. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 750 mg (yield: 93%) of the title compound. Melting point: 199-200° C. (ethyl acetate-hexane).
Reaction SMILES: Br[CH2:2]Br.[CH3:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[C:6]=1[OH:12]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:4][C:5]1[C:6]2[O:12][CH2:2][O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(O)c1O
Reactant: BrCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Product: Cc1cccc2c1OCO2

Procedure:
11.6 g Adogen 464 and 7 mL of dibromomethane were refluxed in 50 mL of H20 for 0.5 hours under argon. 3-Methylcatechol (8.89 g, 71.6 mmol) was added over 2 hours and the mixture refluxed for an additional 1 hour. Distillation of the product from the reaction mixture afforded the title compound as a yellow oil: HRMS m/e 136.0524 (calc'd for C8H8O2, 136.0524).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH:26]([P:35](=[O:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:12]1([S:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH:26]([P:35](=[O:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOP(=O)(OCC)C(NCCCCCCSc1ccccc1)P(=O)(OCC)OCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(NCCCCCCS(=O)c1ccccc1)P(=O)(OCC)OCC
Yield: 82.6 %

Procedure:
m-Chloroperbenzoic acid (2.62 g) in limited amounts was added to a solution of tetraethyl 6-(phenylthio)hexylaminomethylenebisphosphonate (6.85 g) in dichloromethane (100 ml) under ice-cooling over 30 minutes. The reaction mixture was stirred under ice-cooling for 3 hours, and then washed with a saturated aqueous solution of sodium bicarbonate and water and dried (MgSO4). The solvent was distilled off under reduced pressure. The residual oil was subjected to column chromatography on silica gel. Tetraethyl 6-(phenylsulfinyl)hexylaminomethylenebisphosphonate (5.84 g, 82.6%) was obtained as an oil from the fractions obtained by elution with ethyl acetate-chloroform-methanol (10:10:1, v/v).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2cccnc2)c2snc(-c3ccccc3)c2c1O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a solution of 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (180 mg, 0.47 mmol) in DMF (2.37 mL) was added 3-(tributylstannyl)pyridine (349 mg, 0.95 mmol) and PdCl2(PPh3)2 (33.3 mg, 0.047 mmol). The reaction mixture was stirred at 120° C. for 30 min. After cooling to r. t. the mixture was partitioned between water (150 mL) and EtOAc (150 mL). The organic layer was washed with brine, water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2 gave the title compound as white solid (28 mg): MS (m/z) 378.1 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]([CH3:11])=[CH2:10].[Br:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20]>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:8][C:9]([CH3:11])=[CH2:10]
Reactant: Oc1ccc(F)cc1Br
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(F)cc1Br
Temperature: 60 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Potassium carbonate (829 mg, 6.00 mmol) and 3-chloro-2-methyl-1-propene (0.591 mL, 6.00 mmol) were added to a solution (25 mL) of 2-bromo-4-fluorophenol (955 mg, 5.00 mmol) in DMF, and stirred at 60° C. overnight. The solvent was distilled away under reduced pressure, and after diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[S:16].[CH3:21]I>ClCCl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[S:16][CH3:21]
Reactant: COc1ccccc1CN1Cc2ccccc2NC1=S
Reactant: CI
Solvent: ClCCl
Product: COc1ccccc1CN1Cc2ccccc2N=C1SC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.0 g (10.55 mmol) 3-(2-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-thione was dissolved in 40 mL dichloromethane, 1.31 mL CH3I was added and stirred for approx. 12 hours at room temperature. The reaction mixture was evaporated until dry and the resulting residue was stirred with a mixture of n-pentane/diethyl ether; 3.1 g white solids.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[CH3:20][C:21]([CH3:23])=O>>[CH3:20][C:21]1([CH3:23])[O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[O:4]1
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)OC(=O)CC(=O)O1

Procedure:
As described in CA 2:14217, 52 g. of malonic acid, 60 ml. of acetic anhydride, 1.5 ml. of sulfuric acid and 40 ml. of acetone were stirred at 0° for 8 hours. The solid was filtered and washed with water, giving 37 g. of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: Nc1cnccn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 3.4 %

Procedure:
To a solution of aminopyrazine (2.00 g, 21.0 mmol) and pyridine (5.10 ml, 63.1 mmol) in tetrahydrofuran was added 2,2,2-trichloroethyl chloroformate (4.34 ml, 31.5 mmol) with ice-cooling, the mixture was stirred for 2 hours with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (193 mg, 3.4%) as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6]CC)=[O:5].[NH:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[O:30])[C:19]4[C:24]([S:25](=[O:29])(=[O:28])[C:26]=3[CH:27]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:12][N:11]=[N:10]1.[OH-].[Na+]>CC(C)=O.O>[C:4]([CH2:3][CH2:2][N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[O:30])[C:19]4[C:24]([S:25](=[O:28])(=[O:29])[C:26]=3[CH:27]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:12][N:11]=[N:10]1)([OH:6])=[O:5]
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Reactant: CCOC(=O)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CCn1nnnc1-c1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O

Procedure:
Ethyl 3-bromopropionate (9.05 g) in acetone (70 ml) was added to 3-(5-tetrazolyl)thioxanthone-10,10-dioxide (15.6 g) and sodium hydroxide (2.0 g) in water (15 ml). The mixture was boiled under reflux for 8 hr. On cooling the ester product crystallised out and was filtered off, washed with dilute sodium bicarbonate solution, and recrystallised from ethanol, m.p. 143°-145° C. The ester (4.5 g) was boiled with a mixture of concentrated hydrochloric acid (40 ml) and acetic acid (120 ml) for 3 hr. On cooling, 3-((2-carboxyethyl)-5-tetrazolyl)thioxanthone-10,10-dioxide crystallised out and was filtered off and washed with water, m.p. 206°-207° C.
Reaction SMILES: Cl.C(N(CC)CC)C.[N-:9]=[N+:10]=[N-:11].[Na+].[C:13]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])#[N:14]>CN1CCCC1=O>[NH:9]1[C:13]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])=[N:14][N:11]=[N:10]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1C=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1-c1nnn[nH]1
Temperature: 110 °C

Procedure:
20.3 g (147 mmol) of triethylamine hydrochloride and 21.0 g (322 mmol) of sodium azide are added to a solution of 14.0 g (107 mmol) of 2-cyano-benzaldehyde in 350 ml of 1-methyl-2-pyrrolidone and heated at 110° C. for 3 hours (argon atmosphere). The black reaction solution is poured into 0.6 liter of ice/37% HCl (20:1) and stirred thoroughly to complete the reaction. Extraction with 3 portions of ethyl acetate, washing the organic phases with 3× water and brine, drying (Na2SO4), concentration by evaporation and stirring in diethyl ether yield 2-(tetrazol-5-yl)-benzaldehyde; m.p. 130° C.; TLC: Rf=0.10 (CHCl3/methano/H2O/acetic acid=85:13:1.5:0.5).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14](=[NH:18])OCC)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:26]([NH:28][NH2:29])=[O:27]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([NH:29][NH:28][CH:26]=[O:27])=[NH:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=N)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: NNC=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NNC=O)c1ccc(-c2ccc(Cl)cc2)o1
Reaction time: 0.25 h

Procedure:
To a mixture of 120 g (0.42 mole) of ethyl 5-(4-chlorophenyl)-2-furimidate hydrochloride in 700 ml of absolute ethanol was added dropwise 62 ml (0.46 mole) of triethylamine at a temperature of 2°-4° while under a nitrogen atmosphere. To this stirring mixture was added portionwise 28 g (0.47 mole) of formic acid hydrazide while maintaining the temperature at 4°-7° by means of an ice bath. The mixture was kept at 5°-7° for 15 minutes, allowed to warm to 23° over a 21/2 hour period, cooled to 10°, filtered, and washed in stirring S.D.A #32 to yield 52 g (47%). An analytical sample was prepared by drying a sample in a vacuum pistol with refluxing chloroform, m.p. 155°-157° (Mel-Temp).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=3)[CH2:34][CH2:33]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=S)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 70.8 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.
Reaction SMILES: CC1C[O:5][C:4]2([CH2:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([CH3:15])=[CH:7]2)O1.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].O.[Li]>CCCCCC>[CH2:16]([C:9]1([OH:14])[C:10]([CH3:12])([CH3:13])[CH2:11][C:4](=[O:5])[CH:7]=[C:8]1[CH3:15])[CH2:17][CH2:18][CH3:19]
Reactant: CC1=CC2(CC(C)(C)C1=O)OCC(C)O2
Reactant: [Li]CCCC
Agent: [Li]
Solvent: CCCCCC
Solvent: O
Product: CCCCC1(O)C(C)=CC(=O)CC1(C)C
Reaction time: 0.25 h

Procedure:
A solution of 20 g of 2,7,9,9-tetramethyl-1,4-dioxaspiro-[4,5]dec-6-en-8-one (prepared by the method of Example III) in hexane is stirred while a solution of n-butyl lithium in hexane is added dropwise. When no additional exotherm occurred the addition is stopped and the mixture is stirred for about 15 minutes. Water is added with stirring to hydrolyze the lithium salt. The organic layer is separated and the hexane is allowed to evaporate, leaving oily crystals which are recrystallized from cyclohexane yielding 10 g of 4-butyl-4-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one, m.p. 90°-93° C. The compound exhibits the following spectral characteristics:
Reaction SMILES: [Br:1]C1CC(=O)NC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:14]=[N:15][CH:16]=1>C(#N)C>[Br:1][C:16]1[N:15]=[CH:14][C:13]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]2)=[CH:12][C:11]=1[O:10][CH3:9]
Reactant: O=C1CC(Br)C(=O)N1
Reactant: COc1cncc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: CC#N
Product: COc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cnc1Br
Reaction time: 0.33 h
Yield: 57 %

Procedure:
Bromosuccinimide (3.56 g, 20.0 mmol) was added to a mixture of 1-(5-methoxy-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (6.14 g, 20.0 mmol) and acetonitrile (200 ml) at room-temperature and stirred for 20 minutes. The mixture was evaporated and purified by chromatography on silica gel with ethyl acetate and petroleum (1:1) as solvent and gave 4.4 g, 57% of the title compound.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[H][H]>C(O)C.C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[S:1]1[C:5]([C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)c1cc2ccccc2s1
Reactant: [H][H]
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(O)CCCCCC[C@H]1C(=O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)c1cc2ccccc2s1

Procedure:
(Z)-7-((1R,2R,3R)-2-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-hydroxyprop-1-enyl)-3-hydroxy-5-oxocyclopentyl)hept-5-enoic acid (Example 7, 1 molar equivalent) is dissolved in a 3:2 mixture of ethanol and benzene (0.01 M) under a nitrogen atmosphere. Wilkinson's catalyst (30% by weight relative to starting material) is added and hydrogen gas is introduced. The hydrogen uptake is monitored and upon theoretical consumption, the solvents are removed under reduced pressure and the residue is dissolved in a minimal amount of ethyl acetate containing 1% acetic acid. The crude product is purified using a filtration column on silica gel, eluted with 0.4% acetic acid in ethyl acetate. A second flash silica column eluted with an isopropanol-hexanes-acetic acid solvent system affords the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]12[C:11]([CH3:13])([CH3:12])[CH:8]([CH2:9][CH2:10]1)[C:6](=[O:7])[C:4]2=[O:5].[C:14]([C:18]1[CH:23]=C(C)C=C(C(C)(C)C)[C:19]=1[OH:29])(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)C(C)=C>O1CCOCC1>[C:19]([O:1][CH2:2][C:3]12[C:11]([CH3:13])([CH3:12])[CH:8]([CH2:9][CH2:10]1)[C:6](=[O:7])[C:4]2=[O:5])(=[O:29])[C:18]([CH3:23])=[CH2:14]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)C2CCC1(CO)C(=O)C2=O
Agent: C=C(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC12CCC(C(=O)C1=O)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Analogously to L. Angiolini et al., 2000, Macromol. Chem. Phys. 201, 2646, a mixture of 10 mmol (1.82 g) of 10-hydroxycamphorquinone, 10 mg of 2,6-di-tert.butyl-4-methylphenol (inhibitor), 1.5 ml of dry triethylamine (TEA) and 50 ml of absolute 1,4-dioxane, under argon and with exclusion of daylight, was added dropwise at 0° C. to a stirred solution of 11 mmol (1.15 g) of methacrylic acid chloride, dissolved in 20 ml of 1,4-dioxane. There followed stirring for 2 h at room temperature and 2 h under reflux. The reaction mixture was filtered off from the formed TEA-HCl, diluted with diethyl ether, washed with 5% sodium bicarbonate solution and with water. After drying over anhydrous Na2SO4 the solution was concentrated to dryness in a rotary evaporator and the solid crude product recrystallized from toluene/n-hexane (20:80 v/v). 1.55 g (62% of the theory) of yellow crystals of 10-methacryloyloxycamphorquinone MACQ was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([CH:22]=O)[NH:18][C:17]=2[CH:16]=[CH:15][C:14]=1[CH3:24].CC(O)=O.[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([CH2:22][NH:11][C:10]3[CH:9]=[CH:8][NH:7][C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:18][C:17]=2[CH:16]=[CH:15][C:14]=1[CH3:24]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: Cc1ccc2[nH]c(C=O)nc2c1C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]ccc1NCc1nc2c(C)c(C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
3-Amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.077 g, 0.5 mmol), 4,5-dimethyl-1H-benzimidazole-2-carbaldehyde (0.130 g, 0.75 mmol) and HOAc (0.045 g, 0.75 mmol) were stirred in methanol (4 mL) followed by addition of NaCNBH3. The resulting mixture was stirred at r.t. for 16 h. The reaction mixture was neutralized with 2M NaOH and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and extracted with water. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate), obtaining a white solid, 0.043 g (27%) of the title compound, as a tautomeric mixture (1:1).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[CH2:4][CH2:5][OH:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:6][CH2:5][CH2:4][CH:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1([CH3:11])[CH3:1])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)C=CC=CC1CCO
Solvent: c1ccncc1
Product: CC(=O)OCCC1C=CC=CC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 2,2-dimethylphenethyl alcohol (118.0 g, 0.786 mol) in pyridine (700 mL). Add, by dropwise addition, acetic anhydride (222 mL, 240.7 g, 2.358 mol) and stir overnight at room temperature. Evaporate the solvent in vacuo and purify by distillation to give the title compound as a clear colorless oil; bp 75° C. @0.4 mmHg.
Reaction SMILES: CO[C:3]1[CH:27]=[CH:26][C:25](C)=[CH:24][C:4]=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6].Cl.FC(F)(F)C1N=C[C:35]([NH:38][C@H:39]2[CH2:43][CH2:42]C[C@@H]2N)=[N:36]C=1.N1C=CC=NC=1C1C=CC=CC=1C(O)=O>>[N:38]1[CH:39]=[CH:43][CH:42]=[N:36][C:35]=1[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][N:15]=1)=[O:6]
Reactant: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C(O)c1ccccc1-c1ncccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 75 mg, 0.27 mmol) and 2-(pyrimidin-2-yl)benzoic acid (CAS number 400892-62-8; 64 mg, 0.32 mmol) to afford the title compound.