Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)O)=[C:17]([CH3:30])[CH:16]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][C:17]=1[CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1
Reactant: Cc1cc(F)ccc1C(O)c1ccc(F)cc1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from Example 11A and 733 mg (2.56 mmol) of the compound from Example 82A in analogy to the synthesis of the compound from Example 278. A difference was that stirring at 80° C. was for only 4 h. 428 mg (39% of theory) of the target compound were obtained.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:37][CH:36]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22]CC)=[O:21])[CH:13]=[CH:12][C:11]1=2)C.[OH-].[K+].C(O)(=O)C.Cl>O1CCOCC1.O>[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:37][CH:36]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([OH:22])=[O:21])[CH:13]=[CH:12][C:11]1=2)([OH:49])=[O:3]
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(CCc2ccccc2)cc1)C1CCCc2nc(C(=O)OCC)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCCN(CCc1ccccc1OCc1ccc(CCc2ccccc2)cc1)C1CCCc2nc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
259 mg (0.39 mmol) of ethyl 5-{(5-ethoxy-5-oxopentyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}-phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 50A) were taken up in 4 ml of dioxane, 2 ml of a 2 M solution of potassium hydroxide in water were added and the mixture was stirred at room temperature overnight. After the reaction had gone to completio, the reaction mixture was acidified slightly using 0.75 ml of acetic acid and 1 N of hydrochloric acid and then concentrated to dryness. The residue obtained was purified by preparative HPLC. This gave 183 mg (0.30 mmol, 77% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(O)C.COCCOC.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccccc1-c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 20 h
Yield: 70.9 %

Procedure:
To a solution of 2-bromobenzaldehyde (18.0 g, 97.0 mmol) and 4-chloro-phenylboronic acid (19.0 g, 122 mmol) in a 1:1 mixture of ethanol/DME (400 mL) is added a solution of potassium carbonate (26.9 g, 195 mmol) in water (100 mL), and the reaction mixture is purged with nitrogen for 30 minutes. Tetrakis(triphenyl-phosphine)palladium (5.62 g, 4.86 mmol) is then added, and the reaction is purged again with nitrogen for 20 minutes. The pale yellow-green solution is heated to 75° C. and stirred for 20 hours. The reaction is then cooled to room temperature, diluted with ethyl acetate (200 mL), and filtered through a ZAPCAP filter. The filtrate is washed with brine (400 mL) and the aqueous layer is back-extracted with ethyl acetate (2×200 mL). The combined organic layers are dried over MgSO4 and concentrated to afford an orange oily solid. This crude material is purified via flash chromatography on silica gel (0-20% EtOAd heptanes) to afford the title compound (14.9 g, 71% yield). 1H NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.68 (t, J=6.2 Hz, 1H), 7.54 (t, J=7.4 Hz, 1H), 7.49 (d, J=9.4 Hz, 2H), 7.45 (d, J=9.1 Hz, 1H), 7.34 (d, J=8.5 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.C([Li])CCC.CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1.CCCCC>[F:11][C:4]1[CH:3]=[C:2]([CH:19]=[O:20])[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c2occc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=Cc1cc(F)cc2ccoc12
Temperature: -97.5 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
7-Bromo-5-fluoro-benzofuran (7 g, 32 mmol, Step B) was dissolved in a mixture of tetrahydrofuran (350 mL) and pentane (100 mL), cooled to −95 to −100° C., and treated with n-butyl lithium (14 mL, 35 mmol, 2.5M in hexane, Aldrich). After stirring for 5 minutes, a solution of dimethylformamide (5 mL) in tetrahydrofuran (15 mL) was added dropwise and the reaction temperature raised to −20° C. This was treated with aqueous ammonium chloride (50 mL) and stirred for 0.5 hour at ambient temperature. The reaction mixture was concentrated in vacuo and diluted with hexane. The organic fraction was washed with water and dried (Na2SO4). Removal of solvent afforded crude 5-fluoro-benzofuran-7-carbaldehyde (˜30%) as an oil. Purification was by silica gel chromatography (5–10% ethyl ether/hexane). HRMS, observed: 163.0201; Calcd for (M+H)+: 163.0195
Reaction SMILES: [H-].[Na+].[H][H].BrCCCCC(OCC)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](/[C:21](=[N:27]\[O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])/[C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)[CH:16]=1>CN(C)C=O>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](/[C:21](=[N:27]/[O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])/[C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)[CH:16]=1
Reactant: CCOC(=O)CCCCO/N=C(\c1cccnc1)c1ccsc1
Reactant: [H][H]
Agent: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCO/N=C(/c1cccnc1)c1ccsc1
Reaction time: 18 h
Yield: 30 %

Procedure:
To a stirred mixture of 10.2 parts of (E+Z)-(3-pyridinyl) (3-thienyl)methanone, oxime and 67.5 parts of N,N-dimethylformamide were added portionwise 2.4 parts of a sodium hydride dispersion 50% at room temperature during a period of 15 minutes. Upon completion, stirring was continued till hydrogen evolution had ceased. 12.5 Parts of ethyl 5-bromopentanoate were added dropwise during a period of 10 minutes. Upon complete addition, stirring was continued for 18 hours at room temperature. After evaporation in vacuo, the residue was stirred in water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel using a mixture of trichloromethane and ethyl acetate (90:10 by volume) as eluent. The first fraction was collected and the eluent was evaporated in vacuo, yielding 5.5. parts (33.0%) of ethyl (E)-5-[[[(3-pyridinyl) (3-thienyl)methylen]amino]oxy]pentanoate as a residue (compound 37). The second fraction was collected and the eluent was evaporated in vacuo, yielding 5 parts (30.0%) of ethyl (Z)-5-[[[(3-pyridinyl) (3-thienyl)methylen]amino]oxy]pentanoate as a residue (compound 38).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[N:27])[CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1.N.[H][H]>[Ni].CO>[NH2:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:17]2[N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:10]3[C:15]([N:16]=2)=[CH:14][N:13]=[CH:12][N:11]=3)[CH2:24][CH2:23]1
Reactant: N#CCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Yield: 87.5 %

Procedure:
A mixture of 18.2 parts of 4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidineacetonitrile and 240 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at a temperature below 20° C. with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 16 parts (87.5%) of N-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine; mp. 146.1° C. (compound 155).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C([Li])CCC.[CH3:11][C:12]([CH3:20])=[CH:13][CH2:14][CH2:15][C:16]([CH:18]=[CH2:19])=[CH2:17].C(C(CC)/C(/C)=C/CC/C(/C)=C/CN)C.C(N)/C=C(/CCC=C(C)C)\C>CCCCCC>[CH2:1]([N:3]([CH2:19]/[CH:18]=[C:16](/[CH2:15][CH2:14][CH:13]=[C:12]([CH3:20])[CH3:11])\[CH3:17])[CH2:4][CH3:5])[CH3:2]
Reactant: C=CC(=C)CCC=C(C)C
Reactant: CCNCC
Agent: CC(C)=CCC/C(C)=C/CN
Agent: CCC(CC)/C(C)=C/CC/C(C)=C/CN
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCN(CC)C/C=C(\C)CCC=C(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Dry diethylamine (84 ml, 0.816 mole) was charged into a 500 ml 3 necked flask equipped with reflux condenser, thermometer, addition funnel and magnetic stirrer. The flask was swept out with dry nitrogen and maintained under a nitrogen blanket. Butyl lithium (16.6 ml, 2.2 M) in hexane was then added and the temperature raised to 50° C. After 15 minutes 200 ml 85% myrcene (1 mole) was added. The mixture exothermed and was cooled to 60°. After 4 hours at 60°, gas chromatography indicated that the amine had been converted to virtually a single product in high yield. Distillation gave a fraction boiling at 108° C./7 mm which was identified as diethylgeranylamine. The yield was 148.7 g (87% based on the amine used) of a product which was 96% "geranyl amine". (See Table I).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[C:4]([C:17]([O:19]CC)=O)=[C:5]([C:12](OCC)=[O:13])[NH:6]2.O.[NH2:23][NH2:24]>C(O)C>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]2[C:4]3[C:17](=[O:19])[N:24]=[N:23][C:12](=[O:13])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: NN
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C(=O)OCC
Solvent: O
Solvent: CCO
Product: O=C1N=NC(=O)c2c1[nH]c1cc(Cl)cc(Cl)c21
Temperature: 25 °C
Yield: 90 %

Procedure:
To a stirred solution of diethyl 4,6-dichloroindole-2,3-dicarboxylate (3.22 g, 9.8 mM) in ethanol (20 mL) was added hydrazine hydrate (14.2 mL, 294 mM). The solution was refluxed for 3 hours during which time a precipitate formed. The reaction mixture was then cooled to room temperature, the solid was filtered and heated to reflux in 3N HCl. After several minutes, the mixture was cooled to room temperature and the solid was filtered, washed with ethanol, and dried. This afforded the titled product as a white solid (2.6 g, 90%), mp >300° C. NMR (d6 -DMSO): 13.02 (br s, 1H), 11.72 (br s, 2H), 7.54 (s, 1H), 7.40 (s, 1H). MS(CI): 271(M+1).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Cl.[CH:11]1([CH:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=2)[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>COCCOC>[CH:11]1([CH:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:24])=[CH:21][CH:20]=2)[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)CC(C)=O
Reactant: CC(Nc1ccc(C(=O)Cl)cc1)C1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(C(C)=O)C(=O)c1ccc(NC(C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 28.4 g. of 2,4-pentanedione and 20 ml. of 1,2-dimethoxyethane is added to a suspension of 13.6 g. of sodium hydride in 220 ml. of 1,2-dimethoxyethane under argon. A solution of 28.7 g. of 4-(1-cyclopentylethylamino)-benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is stirred at room temperature for 12 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue is then chromatographed over silica gel to yield 3-[4'-(1-cyclopentylethylamino)benzoyl]-2,4-pentanedione.
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1>O>[C:1]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:16])[C:1]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:16]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Solvent: O
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1

Procedure:
400 parts of distilled water were added to 200 parts of diphenyl carbonate, obtained through the decarbonylation reaction of diphenyl oxalate using triphenyl phosphine and bromine (Br2) as catalysts, and the mixture was heated to 90° C. and stirred for 1 hour. This washing step was repeated twice to obtain diphenyl carbonate containing 1.7 ppm of hydrolyzable bromine. An ester interchange reaction between this diphenyl carbonate and bisphenol A was carried out in the same manner as in Example 1 except that a disodium salt of bisphenol A was used in place of sodium hydroxide as an ester interchange catalyst in an amount of 2.0×10−6 mole, in terms of sodium, based on bisphenol A, to synthesize polycarbonate. A pellet of this polycarbonate was used for the measurement of its physical properties. The conditions and results are shown in Tables III-A and III-B below.
Reaction SMILES: F[C:2](F)(F)C1C=C(C=CC=1)C=O.[CH:13]1([CH:19]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:20]([NH:22][C@H:23]2[C@H:30]3[C@H:26]([CH2:27][NH:28][CH2:29]3)[CH2:25][CH2:24]2)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:37]1([CH:43]([CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)[C:44](N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:31]1([CH:19]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:20]([NH:22][C@H:23]2[C@H:30]3[C@H:26]([CH2:27][N:28]([CH2:2][CH2:44][CH:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH2:29]3)[CH2:25][CH2:24]2)=[O:21])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(N[C@@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: O=C(N[C@@H]1CC[C@H]2CN(CCC(c3ccccc3)c3ccccc3)C[C@H]21)C(C1CCCCC1)C1CCCCC1

Procedure:
The title compound was prepared by substituting 3,3-diphenylpropanol for 3-(trifluoromethyl)benzaldehyde and 2,2-dicyclohexyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide from Example 74 for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.10 (d, J=7.7, 1H), 7.45 (d, J=7.3, 2H), 7.42 (d, J=7.1, 3H), 7.38-7.30 (m, 5H), 4.56-4.48 (m, 1H), 4.27 (t, J=7.5, 1H), 2.92-2.86 (m, 1H), 2.59-2.48 (m, J=6.7, 14.0, 2H), 2.38-2.26 (m, 5H), 2.21-2.12 (m, 2H), 2.05 (t, J=7.4, 1H), 1.97 (dd, J=8.3, 17.0, 2H), 1.94-1.85 (m, 4H), 1.81 (d, J=11.8, 2H), 1.72 (d, J=13.2, 4H), 1.66 (dd, J=7.4, 11.8, 1H), 1.61 (d, J=12.6, 2H), 1.48 (ddd, J=3.4, 12.8, 15.5, 3H), 1.30-1.19 (m, 4H), 1.19-1.06 (m, 4H); MS (ESI+) m/z 527 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:7][S:8]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:14][CH:15]=1)(=[O:10])=[O:9])([CH3:6])[C:3]([OH:5])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:57][Si:58]([CH3:64])([CH3:63])[CH2:59][CH2:60][O:61][NH2:62]>C(Cl)Cl>[CH3:6][C:2]([NH:7][S:8]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:14][CH:15]=1)(=[O:10])=[O:9])([CH3:1])[C:3]([NH:62][O:61][CH2:60][CH2:59][Si:58]([CH3:64])([CH3:63])[CH3:57])=[O:5]
Reactant: C[Si](C)(C)CCON
Reactant: CC(C)(NS(=O)(=O)c1ccc(-c2ccccn2)s1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NS(=O)(=O)c1ccc(-c2ccccn2)s1)C(=O)NOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
To a solution of 2-methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)-propionic acid (1.60 grams, 4.91 mmole) in methylene chloride (160 mL) was added triethylamine (2.3 mL, 16.5 mmole), (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (2.4 grams, 5.41 mmole) and O-(2-trimethylsilylethyl)hydroxylamine hydrochloride (0.92 grams, 5.41 mmole). The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed with water, aqueous saturated sodium bicarbonate solution, and brine. After drying over magnesium sulfate, the solvent was evaporated to afford a white foam from which the desired product, 2-methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)-N-(2-trimethylsilanylethoxy)-propionamide (220 mg, 10%), a white solid, was isolated by chromatography on silica gel eluting with 3:2 ethyl acetate/hexanes.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C@@H:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]1=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.Cl.C(OCC)(=O)C>CCOCC>[CH3:6][NH:8][CH2:9][CH2:10][C@@H:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:19]1=[O:32])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(CC[C@H](c1ccccc1)N1C(=O)C2(CCCCC2)c2ccccc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CNCC[C@H](c1ccccc1)N1C(=O)C2(CCCCC2)c2ccccc21
Reaction time: 16 h
Yield: 95.7 %

Procedure:
1′-[(1R)-3-(tert-butoxycarbonyl-methylamino)-1-phenylpropyl] spiro [cyclohexane-1,3′-indol]-2′(1′H)-one (70 mg, 0.15 mmol) was dissolved in ether (5 mL) and 2N HCl in ethyl acetate (0.3 mL, 0.6 mmol) was added. The mixture was stirred 16 hours then concentrated under a stream of nitrogen. The residue was purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 50 mg of 1′-[(1R)-3-(methylamino)-1-phenylpropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one. The freebase was dissolved in ether (2 mL) and treated with 1N hydrochloric acid in ether (0.14 mL, 0.14 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give 56 mg of 1′-[(1R)-3-(methylamino)-1-phenylpropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1.[CH3:22][N:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([CH2:2][N:25]4[C:26](=[O:28])[CH2:27][N:23]([CH3:22])[C:24]4=[O:29])=[CH:4][CH:5]=3)[N:10]=[C:9]([C:13]#[N:14])[CH:8]=2)=[CH:16][CH:17]=1
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Reactant: CN1CC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CC(=O)N(Cc2ccc3c(-c4ccc(F)cc4)cc(C#N)nc3c2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
7-(Bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 50.0 mg, 0.147 mmol, 1.0 equiv.), 1-methylimidazolidine-2,4-dione (18.4 mg, 0.161 mmol, 1.1 equiv.) and cesium carbonate (95.0 mg, 0.293 mmol, 2.0 equiv.) were combined into 1.0 ml of DMF. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was filtered and the filtrate was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(4-fluorophenyl)-7-[(3-methyl-2,5-dioxoimidazolidin-1-yl)methyl]quinoline-2-carbonitrile (2-2, 48.0 mg, 87.0%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.205 (d, J=1.09 Hz, 1H); 7.941 (d, J=8.79 Hz, 1H); 7.681 (dd, J1=8.79 Hz, JZ=1.83 Hz, 1H); 7.647 (s, 1H); 7.454-7.503 (m, 2H); 7.251-7.309 (m, 2H); 4.935 (s, 2H); 4.049 (s, 2H); 3.057 (s, 3H). LRMS m/z (M+H)+ 375.1 found, 375.1 required.
Reaction SMILES: [O:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>CC(O)=O.CCO>[O:1]([C:8]1[CH2:13][CH2:12][C:11]2[C:14]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:26][NH:27][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccccc1)C1CCC(Oc2ccccc2)=CC1=O
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: C(=Cc1n[nH]c2c1CCC(Oc1ccccc1)=C2)c1ccccc1
Temperature: 70 °C
Yield: 36.4 %

Procedure:
To a stirred solution of 3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2-enone (1.13 g, 3.55 mmol) in 20 mL of HOAc/EtOH(1:1) was added hydrazine monohydrate (0.21 mL, 4.3 mmol). The reaction was heated at 70° C. for 3 h, cooled and poured cautiously into saturated Na HCO3 solution and extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1) to give 6-phenoxy-3-styryl-4,5-dihydro-1H-indazole (3) as an off-white solid (406 mg, 36%): 1H NMR (DMSO-d6) δ 2.64 (t, 2H, J=8.0 Hz), 2.95 (t, 2H, J=8.0 Hz), 5.46 (s, 1H), 7.04 (AB, 2H, J=16.8 Hz), 7.15 (d, 2H, J=8.1 Hz), 7.25 (m, 2H), 7.42 (m, 4H), 7.55 (d, 2H, J=7.7 Hz), 12.44 (s, 1H). Anal. Calc. for C2H18N2O.0.2H2O: C, 79.32; H, 5.83, N, 8.81. Found: C, 79.36; H, 5.85; N, 8.84.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([N:28]([CH3:30])[CH3:29])(=[O:32])=[O:31])[CH:25]=[CH:26][C:18]=3[Cl:17])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CN(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(=O)(=O)N(C)C)ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-dimethylsulfamoyl-benzoic acid (CAS: 37088-27-0; BE 620741) (64%, light yellow foam, MS (m/e): 468.1 (M+H+, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]([CH3:20])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12]I>>[CH3:10][C:11]([CH3:20])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1O
Reactant: CCCCCCC(C)(C)CI
Product: CCCCCCC(C)(C)COc1ccccc1C=O

Procedure:
2-Hydroxybenzaldehyde was condensed with 2,2-dimethyl-1-iodo octane to yield 2-(2,2-dimethyl octyloxy) benzaldehyde which was reduced to 2-(2,2-dimethyl, octyloxy)benzyl alcohol and then converted to [[2-(2,2-dimethyloctyloxy)phenyl]methyl]triphenylphosphonium bromide as in Example 1. Condensation of this phosphonium bromide with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 followed by hydrolysis, as in Example 5, gave the (All-E)-3,7-Dimethyl-9-[2-[(2,2dimethyl-octyl]phenyl]-2,4,5,8-non-atetraenoic acid mp 113-117° (from dichloromethane/hexane mixture).