Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Br)nc1
Reactant: Nc1ccc(F)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(F)cc1)c1ccc(Br)nc1
Reaction time: 12 h
Yield: 71.8 %

Procedure:
To a suspension of 6-bromonicotinoyl chloride (0.5 g, 2.5 mmol) in dry chloroform (10 mL) was added 4-fluoroaniline (0.33 mL, 3.5 mmol) and 2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, (0.85 g, 3.5 mmol). The mixture was stirred for 12 h, diluted with hexanes and the solids isolated by filtration. Purification by trituration using ethyl acetate/hexanes gave 0.53 g (73%) of the desired product as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.87 (m, 1H), 8.20 (m, 1H), 7.82 (m, 1H), 7.74 (m, 2H), 7.19 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([C:10]#[N:11])=[C:6]([CH3:9])[C:7]=1I.[N+:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([C:10]#[N:11])=[C:6]([CH3:9])[C:7]=1[C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:29]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COc1c(Br)c(I)c(C)c(C#N)c1NC(=O)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1c(Br)c(-c2cccc([N+](=O)[O-])c2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Temperature: 95 °C
Reaction time: 4 h
Yield: 67.5 %

Procedure:
N-(3-Bromo-6-cyano-4-iodo-2-methoxy-5-methylphenyl)-2,2-dimethylpropionamide (I-6) (965 mg, 2.14 mmol), 3-nitrophenylboronic acid (375 mg, 2.25 mmol), tripotassium phosphate (74-85%, 1.23 g, 4.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (247 mg, 0.214 mmol) were added to a 50-ml eggplant-type flask, followed by purging with nitrogen. N,N-Dimethylformamide (20 ml) was injected into it with a syringe, followed by stirring at 95° C. for 4 hours. After cooling, the reaction liquid was diluted with ethyl acetate, successively washed with saturated brine (×3), 1 N hydrochloric acid, saturated brine, an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried on anhydrous magnesium sulfate, then the solvent was concentrated under reduced pressure to obtain a pale brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1→4:1) to obtain the entitled compound (645 mg, 68%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH:29]12[O:36][CH:33]([CH2:34][CH2:35]1)[CH2:32][NH:31][CH2:30]2>>[F:16][C:14]([F:15])([F:17])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=1)=[CH:3][C:2]([N:31]1[CH2:30][CH:29]3[O:36][CH:33]([CH2:34][CH2:35]3)[CH2:32]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: C1CC2CNCC1O2
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CC4CCC(C3)O4)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Yield: 61 %

Procedure:
The title compound was prepared from 1-[6-bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and 8-oxa-3-aza-bicyclo[3.2.1]octane according to the procedure of example 51. Yield: 61%; MS: m/z=505 (M+H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>CN(C=O)C>[S:14]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cccnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (16.7 g, 114 mmol) in DMF (150 mL) was added to a chilled (0° C.) mixture of dry DMF (300 mL) and sodium hydride (4.88 g, 122 mmol, 60% dispersion in mineral oil). This was stirred at 0° C. for 30 minutes, and a DMF solution (100 mL) of tosyl chloride (21.8 g, 114 mmol) was then added slowly over a ten minute period. The mixture was then allowed to warm to room temperature and stirred for 3 hours. Water (500 mL) was then added, and the solids were collected to give 1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (29.7 g, 87%). 1H NMR (400 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.43-8.49 (m, 2H), 8.08-8.13 (m, 2H), 7.44-7.50 (m, 3H), 2.37 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](Cl)=[N:24][C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=5[CH3:32])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:34]>ClCCl>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=[NH:34])[NH:24][C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=5[CH3:32])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: Cc1ccc(C)c(N=C(Cl)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Solvent: ClCCl
Product: Cc1ccc(C)c(NC(=N)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A mixture of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-N-(2,5-dimethylphenyl)-1-piperidinecarboximidoyl chloride (i.e. the product of Step B) (0.300 g, 0.63 mmol) in dichloromethane (4 mL) was added dropwise to a solution of ammonia in mathanol (7M, 10 ml) which was cooled to 0° C. The reaction mixture was stirred for 2 minutes, concentrated under reduced pressure, and the resulting tan solid portioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give of the title, a compound of the present invention, compound as a foamy white solid (0.25 g).
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:14]2[N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=O.[NH3:21]>CO>[C:15]1([C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][CH2:7][CH2:6][CH:5]([C:3]([NH2:21])=[O:2])[C:14]=3[N:13]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N
Reactant: COC(=O)C1CCCc2ccc(-c3ccccc3)nc21
Solvent: CO
Product: NC(=O)C1CCCc2ccc(-c3ccccc3)nc21
Temperature: 100 °C

Procedure:
Methyl-2-phenyl-5,6,7,8-tetrahydroquinoline-8-carboxylate (4 g.) was dissolved in methanol previously saturated with ammonia (90 ml.) and heated in a bomb at 100° C for 4 days. Removal of the solvent in vacuo gave an oily solid which on recrystallisation from ethyl acetate gave the title compound as colourless needles (1.5 g.) mp 145° C. Found: C, 76.4; H, 6.5; N, 11.1% C16H16N2O requires: C, 76.2; H, 6.4; N, 11.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][N:17]=[C:16]4[C:19]5[C:24]([CH2:25][CH2:26][C:15]=34)=[CH:23][C:22]([CH:27]([OH:30])CO)=[CH:21][CH:20]=5)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+].[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][N:17]=[C:16]4[C:19]5[C:24]([CH2:25][CH2:26][C:15]=34)=[CH:23][C:22]([CH2:27][OH:30])=[CH:21][CH:20]=5)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: OCC(O)c1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: OCc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Reaction time: 0.67 h

Procedure:
To a solution of 1-(3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethane-1,2-diol (Preparation 27C, 0.05 g, 0.118 mmol) in methanol (1.0 mL) at 0° C. was added a solution of sodium periodate (0.030 g, 0.142 mmol) in water (1.0 mL) dropwise. The white heterogeneous reaction mixture was stirred for 40 mins. at the same temperature and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhyd. sodium sulfate and concentrated. The residue was taken in methanol (2 mL) and treated with sodium borohydride (5.35 mg, 0.142 mmol) at room temperature. After 1 h, the reaction was quenched with saturated. aq. sodium bicarbonate. After stirring for 30 min, the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhyd. magnesium sulfate and concentrated to yield (3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][O:12][C:11]3[CH:20]=[CH:21][C:22]([C:24]([O:26]CC)=[O:25])=[CH:23][C:10]2=3)[CH:2]=1.CO.[OH-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][O:12][C:11]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:10]2=3)[CH:2]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(NCc1cccnc1)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(NCc1cccnc1)c1ccccc1CO2

Procedure:
Compound 9a, 3.9 g, obtained in Example 1 was heated to reflux for an hour in a solvent mixture of 200 ml of methanol, 50 ml of water and 10 ml of 10N sodium hydroxide aqueous solution. The solvent was distilled off under reduced pressure and 4N hydrochloric acid aqueous solution was added to the residue to adjust pH to 7. After concentrating under reduced pressure, the residue was subjected to high porous polymer (HP-10; manufactured by Mitsubishi Chemical Industry Co., Ltd.) column chromatography (eluting solvent; methanol) to give 2.5 g of the crude product. The crude product was recrystallized from water to give 2.0 g of the desired product.
Reaction SMILES: C[O-].[Na+].CO.[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])[CH:7]([CH3:9])[CH3:8].O[N:17]=[C:18](Cl)[C:19]1[C:20]([CH3:26])=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25]>C1COCC1>[CH3:26][C:20]1[C:19]([C:18]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:6]([CH:7]([CH3:9])[CH3:8])[O:10][N:17]=2)=[C:24]([CH3:25])[CH:23]=[CH:22][N:21]=1
Reactant: Cc1ccnc(C)c1C(Cl)=NO
Reactant: COC(=O)CC(=O)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2c(C)ccnc2C)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
A 0.5 N solution of sodium methoxide in methanol (2.8 mL, 1.4 mmol) was added to a solution of methyl isobutyrylacetate (0.19 mL, 1.34 mmol) in THF (0.24 mL) at 0° C. A solution of the crude N-hydroxy-2,4-dimethyl-3-pyridinecarboximidoyl chloride (0.22 g, 1.2 mmol) in THF (2.2 mL) was added and the resulting mixture was allowed to warm to room temperature and stir overnight. The solution was concentrated and the residue was partitioned between ethyl acetate and brine. The organic layer was dried with MgSO4, filtered and concentrated. The residue was chromatographed (silica gel, hexane to 3:2 ethyl acetate:hexane) to provide methyl 3-(2,4-dimethyl-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (0.17 g, 52%). ESI-LCMS m/z 275 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2nc(C3CCNCC3)oc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
560 mg tert-butyl 4-(4,5-diphenyloxazol-2-yl)-piperidine-1-carboxylate are placed in 2 ml dichloromethane, then 1.1 ml trifluoroacetic acid are added. The reaction mixture is stirred for 15 hours at ambient temperature, then evaporated to dryness. The residue is combined with toluene and evaporated to dryness again. The residue is combined with diethyl ether and the precipitated solid is suction filtered and dried. 510 mg (V-26) are obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.[CH2:11]([C:18]1[O:19][CH:20]=[C:21]([CH2:23]O)[CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([C:18]1[O:19][CH:20]=[C:21]([CH2:23][Cl:3])[CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1coc(Cc2ccccc2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: ClCc1coc(Cc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 13 g of thionyl chloride in toluene was added dropwise over 15 minutes to a mixture of 15.8 g pyridine and 18.8 g 2-benzyl-4-hydroxymethylfuran, in toluene, at a temperature of 0°-5° C. The mixture was slowly warmed to 80° C. and stirred for 11/2 hours and then cooled in an ice-bath, poured into ice and filtered. The resulting solution was extracted with diethyl ether, washed with water and then with sodium bicarbonate solution, and dried over magnesium sulphate. The solution was then stripped of solvent, yielding a brown oil, which was chromatographed over silica gel using toluene as eluent to give 2-benzyl-4-chloromethylfuran (1A) as a brown oil.
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[NH:6][C:5]1=[S:24])[CH:2]=[CH2:3].C1(C)C=CC(S(O[CH2:35][CH2:36][O:37][CH3:38])(=O)=O)=CC=1.[OH-].[K+].O>C(O)C>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[S:24][CH2:35][CH2:36][O:37][CH3:38])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCn1c(SCCOC)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2

Procedure:
A mixture of 3-allyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (5, 0.100 g, 0.295 mmol), 2-Methoxyethyl p-Toluenesulfonate (0.084 ml, 0.325 mmol), potassium hydroxide (0.025 g, 0.443 mmol) in Ethanol (1.738 ml) was refluxed ON. To the cooled solution, water (1 ml) was added and the mixture was extracted with EtOAc 2×. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to a yellow oil. The product was purified by flash column chromatography eluting with 0 to 2.5% EtOAc in hexane. 1H NMR (500 MHz, CDCl3) δ ppm 8.08, 7.39-7.23, 5.95, 5.33-5.28, 4.71, 3.79, 3.57, 3.45, 3.06, 2.61, 1.75-1.72, 1.60-1.54, 1.42-1.39; MS (EI) m/z 397 (M+1)
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl.[CH3:16]O>>[C:1]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:16])=[O:11])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)NCc1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(C)=O)cc1
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
4-Acetamidomethylbenzoic acid (4.0 g) was dissolved in 0.5% hydrogen chloride-methanol solution (100 ml). The mixture was stirred at 40° C. for 3.5 hr and poured into ice water (300 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-yellow solid (4.3 g). The obtained solid was crystallized from ethyl acetate (50 ml) to give the title compound (3.2 g) as a pale-yellow white crystals, m.p.=110-111° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C[O-].[Na+].[CH3:26][C:27](=[CH:29][CH2:30][CH2:31]/[C:32](=[CH:34]/CO)/[CH3:33])[CH3:28].CO>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:22])[CH2:4][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CCCCCCCCN(CCCCCCCC)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCN(CCCCCCCC)CC(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
To a mixture of N,N-dioctylglycine methyl ester (47.02 g, 150 mmol, 1 eq) in toluene (250 ml) under argon was slowly added some sodium methoxide (1.01 g, 0.019 mol, 0.125 eq) and geraniol (27.3 ml, 158 mmol, 1.05 eq). The mixture was heated under vacuum (10 mm Hg) and the methanol produced by the transesterification reaction is distilled with toluene over one hour after which the reaction appeared completed by 1H NMR. Any remaining toluene is evaporated under vacuum. Diethyl ether was added (200 ml) and the mixture stored at 4° C. for one hour prior to filtration. The filtrate was then concentrated under vacuum yielding to the expected N,N-dioctylglycine geranyl ester as a light yellow oil (quantitative yield).
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][S:8]([C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13])(=[O:10])=[O:9])=[O:5])C.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:15][C:11]([S:8]([CH2:7][C@@H:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([OH:3])=[O:5])(=[O:9])=[O:10])([C:12]([N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)Cl
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)C(C)(C)S(=O)(=O)C[C@@H](Cc2ccccc2)C(=O)O)CC1

Procedure:
In an analogous manner to that described in Example 1, paragraphs (d) and (e), starting from 2-mercaptoisobutyric acid and ethyl 2-benzylacrylate there was obtained (RS)-2-[[2-[(ethoxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride, reaction of which with 1-methylpiperazine analogously to Example 2, paragraph (a), and subsequent enzymatic hydrolysis analogously to Example 6, paragraph (c), yielded (S)-α-[[[1-methyl-1-[(4-methyl-1-piperazinyl)carbonyl]ethyl]sulfonyl]methyl]hydrocinnamic acid, MS: 396 (M)+, as a colourless solid.
Reaction SMILES: [N:1]1([CH2:6][NH:7][C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24]>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]([N:7]([CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C:8]1[N:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[N:13]=1)=[O:28])(=[O:25])=[O:24]
Reactant: Cc1cc(C)nc(NCn2cncn2)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Solvent: CC#N
Product: Cc1cc(C)nc(N(Cn2cncn2)C(=O)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
4 g (0.019 mole) of 2-(1,2,4-triazol-1-ylmethylamino)-4,6-dimethylpyrimidine are suspended in 100 ml of absolute acetonitrile and then 4.3 g (0.019 mole) of 2-chlorophenylsulfonylisocyanate are stirred into the suspension. The batch is stirred for 24 hours at room temperature and the resultant solution is finally concentrated in a rotary evaporator. Crystals of the title compound precipitate and are recrystallized from ethyl acetate, affording 5 g (62% of theory) of the above urea, which melts at 152°-157° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.[CH:19](OCC)=[O:20].CC(C)([O-])C.[K+].Cl>C(OCC)C>[OH:20][CH2:19][CH:3]1[CH2:4][CH2:5][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2=O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(CO)C2=O)CC1
Temperature: -78 °C
Reaction time: 48 h
Yield: 51.4 %

Procedure:
tert-Butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate from Procedure 1, Step G (0.526 g, 2.08 mmol) was dried by evaporating with toluene (10 mL) three times in vacuo, dissolved in methyl-tert-butyl ether (5 mL), and cooled to −78° C. To this solution was added ethyl formate (0.336 mL, 4.15 mmol) and then potassium t-butoxide (0.466 g, 4.16 mmol). After 2 days, the reaction mixture was diluted with diethyl ether, poured into 2N HCl, and extracted three times with diethyl ether. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 0.575 g. The residue was purified by flash chromatography eluting with 45% ethyl acetate/hexanes to give the title compound (0.303 g). MS/EI (acetonitrile/water): m/z 304 (M+1+Na) retention time=2.9 min.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.Cl.N[C@@H](CCN1CC(OC2C=CC([F:48])=CC=2)C1)CO>>[F:48][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(F)cc2)C1
Agent: Cl
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(F)cc3)C2)n(C)n1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 88 except using (S)-2-amino-4-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [H-].[Na+].[C:3]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])[C@H:13]([CH3:30])[CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:31]N(C=O)C>>[C:3]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:31])[CH:21]=2)=[O:19])[C@H:13]([CH3:30])[CH2:12]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2ncccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1cn(C)c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
NaH (2 mg, 60% pure, 0.05 mmol) was added to a solution of compound 5a (10 mg, 0.027 mmol) in DMF. After 30 minutes, Mel (5 mg, 0.035 mmol) was injected into the mixture via syringe. The reaction mixture was stirred for 8 hours at room temperature and quenched with methanol. The mixture was partitioned between ethyl acetate (2 ml) and H2O (2 ml). The aqueous phase was extracted with EtOAc (3×2 ml). The organic layers were combined, dried over anhydrous MgSO4 and concentrated in vacuo to give a crude product which was purified using a Shimadzu automated preparative HPLC System to give compound 21a (2.5 mg, 24%).